Convergent inducers and effectors of T cell paralysis in the tumour microenvironment.


Journal

Nature reviews. Cancer
ISSN: 1474-1768
Titre abrégé: Nat Rev Cancer
Pays: England
ID NLM: 101124168

Informations de publication

Date de publication:
24 Oct 2024
Historique:
accepted: 23 09 2024
medline: 25 10 2024
pubmed: 25 10 2024
entrez: 25 10 2024
Statut: aheadofprint

Résumé

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8

Identifiants

pubmed: 39448877
doi: 10.1038/s41568-024-00761-z
pii: 10.1038/s41568-024-00761-z
doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. Springer Nature Limited.

Références

Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).
pubmed: 31562797 doi: 10.1056/NEJMoa1910836
Gill, J. & Prasad, V. A reality check of the accelerated approval of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 656–658 (2019).
pubmed: 31383994 doi: 10.1038/s41571-019-0260-y
Haslam, A. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open 2, e192535 (2019).
pubmed: 31050774 pmcid: 6503493 doi: 10.1001/jamanetworkopen.2019.2535
Yi, M. et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol. Cancer 21, 28 (2022).
pubmed: 35062949 pmcid: 8780712 doi: 10.1186/s12943-021-01489-2
Daly, R. J., Scott, A. M., Klein, O. & Ernst, M. Enhancing therapeutic anti-cancer responses by combining immune checkpoint and tyrosine kinase inhibition. Mol. Cancer 21, 189 (2022).
pubmed: 36175961 pmcid: 9523960 doi: 10.1186/s12943-022-01656-z
Schoenfeld, A. J. & Hellmann, M. D. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 37, 443–455 (2020).
pubmed: 32289269 pmcid: 7182070 doi: 10.1016/j.ccell.2020.03.017
Finck, A. V., Blanchard, T., Roselle, C. P., Golinelli, G. & June, C. H. Engineered cellular immunotherapies in cancer and beyond. Nat. Med. 28, 678–689 (2022).
pubmed: 35440724 pmcid: 9305718 doi: 10.1038/s41591-022-01765-8
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).
pubmed: 32433532 pmcid: 7238960 doi: 10.1038/s41577-020-0306-5
Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).
pubmed: 31570880 doi: 10.1038/s41577-019-0218-4
Negi, N. & Das, B. K. CNS: not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int. Rev. Immunol. 37, 57–68 (2018).
pubmed: 28961037 doi: 10.1080/08830185.2017.1357719
Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).
pubmed: 7502042 doi: 10.1126/science.270.5239.1189
Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).
pubmed: 28092374 doi: 10.1038/ni.3666
Medawar, P. B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).
pubmed: 18865105 pmcid: 2073079
Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).
pubmed: 25838376 doi: 10.1126/science.aaa6204
Giles, J. R., Globig, A.-M., Kaech, S. M. & Wherry, E. J. CD8
pubmed: 37820583 pmcid: 11237652 doi: 10.1016/j.immuni.2023.09.005
Seo, W., Jerin, C. & Nishikawa, H. Transcriptional regulatory network for the establishment of CD8
pubmed: 33627794 pmcid: 8080584 doi: 10.1038/s12276-021-00568-0
Chopp, L., Redmond, C., O’Shea, J. J. & Schwartz, D. M. From thymus to tissues and tumors: a review of T-cell biology. J. Allergy Clin. Immunol. 151, 81–97 (2023).
pubmed: 36272581 doi: 10.1016/j.jaci.2022.10.011
Yuan, S., Almagro, J. & Fuchs, E. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel. Nat. Rev. Cancer 24, 274–286 (2024).
pubmed: 38347101 pmcid: 11077468 doi: 10.1038/s41568-023-00660-9
de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).
pubmed: 36917948 doi: 10.1016/j.ccell.2023.02.016
Jardim, D. L., Goodman, A., de Melo Gagliato, D. & Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39, 154–173 (2021).
pubmed: 33125859 doi: 10.1016/j.ccell.2020.10.001
Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016). This study shows that neoantigens can be equally abundant in T cell-inflamed versus T cell-uninflamed melanoma tumours, implicating that the immunosuppressive TME, along with cancer cell-intrinsic mechanisms, has a key role in regulating T cell responses.
pubmed: 27837020 pmcid: 5137753 doi: 10.1073/pnas.1609376113
Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172–1187 (2013).
pubmed: 23852952 doi: 10.1093/jnci/djt184
Kraemer, A. I. et al. The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer. Nat. Cancer 4, 608–628 (2023). In this study of lung cancer, neoantigen density does not correlate with T cell inflammation; instead, it is associated with immunoediting in non-inflamed tumours.
pubmed: 37127787 pmcid: 10212769 doi: 10.1038/s43018-023-00548-5
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
pubmed: 21436444 doi: 10.1126/science.1203486
Kalluri, R. & Weinberg, R. A. The basics of epithelial–mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
pubmed: 19487818 pmcid: 2689101 doi: 10.1172/JCI39104
Dongre, A. et al. Direct and indirect regulators of epithelial-mesenchymal transition-mediated immunosuppression in breast carcinomas. Cancer Discov. 11, 1286–1305 (2021). This study in mouse breast cancer models illuminates and functionally validates signals-out that programme immunosuppression in the TME in the context of EMP.
pubmed: 33328216 doi: 10.1158/2159-8290.CD-20-0603
Lüönd, F. et al. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev. Cell 56, 3203–3221.e11 (2021).
pubmed: 34847378 doi: 10.1016/j.devcel.2021.11.006
Gu, Y., Zhang, Z. & Ten Dijke, P. Harnessing epithelial–mesenchymal plasticity to boost cancer immunotherapy. Cell Mol. Immunol. 20, 318–340 (2023).
pubmed: 36823234 pmcid: 10066239 doi: 10.1038/s41423-023-00980-8
Singh, D. & Siddique, H. R. Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance. Cancer Metastasis Rev. 43, 155–173 (2024).
pubmed: 37775641 doi: 10.1007/s10555-023-10141-y
Chen, Z., Han, F., Du, Y., Shi, H. & Zhou, W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther. 8, 70 (2023).
pubmed: 36797231 pmcid: 9935926 doi: 10.1038/s41392-023-01332-8
Semenza, G. L. Targeting intratumoral hypoxia to enhance anti-tumor immunity. Semin. Cancer Biol. 96, 5–10 (2023).
pubmed: 37717718 doi: 10.1016/j.semcancer.2023.09.002
Sadozai, H. et al. High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment. Front. Immunol. 15, 1360629 (2024). This study illustrates the functional effects of hypoxia on programming the TME, implicating various signals-out.
pubmed: 38510243 pmcid: 10951397 doi: 10.3389/fimmu.2024.1360629
Chen, S.-Y., Mamai, O. & Akhurst, R. J. TGFβ: signaling blockade for cancer immunotherapy. Annu. Rev. Cancer Biol. 6, 123–146 (2022).
pubmed: 36382146 doi: 10.1146/annurev-cancerbio-070620-103554
Derynck, R., Turley, S. J. & Akhurst, R. J. TGFβ biology in cancer progression and immunotherapy. Nat. Rev. Clin. Oncol. 18, 9–34 (2021).
pubmed: 32710082 doi: 10.1038/s41571-020-0403-1
Thomas, D. A. & Massagué, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).
pubmed: 16286245 doi: 10.1016/j.ccr.2005.10.012
Gorelik, L. & Flavell, R. A. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat. Med. 7, 1118–1122 (2001). This is a groundbreaking study that functionally validates TGFβ in the suppression of antitumour immunity.
pubmed: 11590434 doi: 10.1038/nm1001-1118
Chen, X.-H. et al. TGF-β and EGF induced HLA-I downregulation is associated with epithelial-mesenchymal transition (EMT) through upregulation of snail in prostate cancer cells. Mol. Immunol. 65, 34–42 (2015).
pubmed: 25618241 doi: 10.1016/j.molimm.2014.12.017
Chen, L. et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun. 5, 5241 (2014). This study describes a signalling pathway governing EMP that induces PDL1 expression, facilitating immune evasion in lung cancer.
pubmed: 25348003 doi: 10.1038/ncomms6241
Mahadevan, K. K. et al. Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8
pubmed: 37625403 pmcid: 10810082 doi: 10.1016/j.devcel.2023.07.025
Mahadevan, K. K. et al. KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8
pubmed: 37625401 pmcid: 10785700 doi: 10.1016/j.ccell.2023.07.002
Briere, D. M. et al. The KRAS
pubmed: 33722854 pmcid: 8444277 doi: 10.1158/1535-7163.MCT-20-0462
Mou, H. et al. Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis. Proc. Natl Acad. Sci. USA 114, 3648–3653 (2017). This article provides further evidence, using a pharmacological knockout, for the programming of immune evasion by oncogenic KRAS.
pubmed: 28320962 pmcid: 5389295 doi: 10.1073/pnas.1620861114
Zhang, Z. et al. A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell 40, 1060–1069.e7 (2022).
pubmed: 36099883 pmcid: 10393267 doi: 10.1016/j.ccell.2022.07.005
Boumelha, J. et al. CRISPR–Cas9 screening identifies KRAS-induced COX2 as a driver of immunotherapy resistance in lung cancer. Cancer Res. 84, 2231–2246 (2024).
pubmed: 38635884 pmcid: 11247323 doi: 10.1158/0008-5472.CAN-23-2627
Lacher, S. B. et al. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8
pubmed: 38658748 pmcid: 11078747 doi: 10.1038/s41586-024-07254-x
Pelly, V. S. et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discov. 11, 2602–2619 (2021). Using pharmacological inhibitors, including nonsteroidal anti-inflammatory drugs, this study reveals the importance of the COX2–PGE
pubmed: 34031121 pmcid: 7611767 doi: 10.1158/2159-8290.CD-20-1815
Bonavita, E. et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity 53, 1215–1229.e8 (2020).
pubmed: 33220234 pmcid: 7772804 doi: 10.1016/j.immuni.2020.10.020
Morotti, M. et al. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 629, 426–434 (2024).
pubmed: 38658764 pmcid: 11078736 doi: 10.1038/s41586-024-07352-w
Tauriello, D. V. F., Sancho, E. & Batlle, E. Overcoming TGFβ-mediated immune evasion in cancer. Nat. Rev. Cancer 22, 25–44 (2022).
pubmed: 34671117 doi: 10.1038/s41568-021-00413-6
Bayne, L. J. et al. Tumor-derived granulocyte–macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).
pubmed: 22698406 pmcid: 3575028 doi: 10.1016/j.ccr.2012.04.025
Yuan, B. et al. Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer. JCI Insight 7, e157788 (2022).
pubmed: 35471938 pmcid: 9220853 doi: 10.1172/jci.insight.157788
Liao, W. et al. KRAS–IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35, 559–572.e7 (2019). This study describes another facet to the roles of oncogenic KRAS in the immunoevasive TME, namely, its induction of CXCL3 that programmes and recruits immunosuppressive myeloid cells within tumours.
pubmed: 30905761 pmcid: 6467776 doi: 10.1016/j.ccell.2019.02.008
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
pubmed: 22698407 pmcid: 3721510 doi: 10.1016/j.ccr.2012.04.024
Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).
pubmed: 22541435 pmcid: 3472002 doi: 10.1016/j.cell.2012.01.058
Zhang, X. et al. The role of tumor metabolic reprogramming in tumor immunity. Int. J. Mol. Sci. 24, 17422 (2023).
pubmed: 38139250 pmcid: 10743965 doi: 10.3390/ijms242417422
De Blander, H. et al. Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial-to-mesenchymal plasticity. Sci. Adv. 10, eadi1736 (2024).
pubmed: 38354248 pmcid: 10866563 doi: 10.1126/sciadv.adi1736
Kortlever, R. M. et al. Myc cooperates with Ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017). This study reveals a new dimension to the well-known cooperativity of KRAS and MYC in tumorigenesis, namely, the programming of an immunosuppressive TME, involving in part CCL9 and IL-33.
pubmed: 29195074 pmcid: 5720393 doi: 10.1016/j.cell.2017.11.013
Khandjian, E. W., Robert, C. & Davidovic, L. FMRP, a multifunctional RNA-binding protein in quest of a new identity. Front. Genet. 13, 976480 (2022).
pubmed: 36035132 pmcid: 9399724 doi: 10.3389/fgene.2022.976480
Malecki, C., Hambly, B. D., Jeremy, R. W. & Robertson, E. N. The RNA-binding fragile-X mental retardation protein and its role beyond the brain. Biophys. Rev. 12, 903–916 (2020).
pubmed: 32654068 pmcid: 7429658 doi: 10.1007/s12551-020-00730-4
Richter, J. D. & Zhao, X. The molecular biology of FMRP: new insights into fragile X syndrome. Nat. Rev. Neurosci. 22, 209–222 (2021).
pubmed: 33608673 pmcid: 8094212 doi: 10.1038/s41583-021-00432-0
Zeng, Q. et al. Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion. Science 378, eabl7207 (2022). This study reveals, via genetic perturbation in multiple tumour models, the unanticipated role of FMRP as a multifaceted master regulator of the immunosuppressive TME, involving in part IL-33, PROS1 and exosomes.
pubmed: 36395212 doi: 10.1126/science.abl7207
Li, L. et al. GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth. Cancer Cell 33, 736–751.e5 (2018).
pubmed: 29606348 pmcid: 5896248 doi: 10.1016/j.ccell.2018.02.011
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
pubmed: 35022204 doi: 10.1158/2159-8290.CD-21-1059
Debnath, J., Gammoh, N. & Ryan, K. M. Autophagy and autophagy-related pathways in cancer. Nat. Rev. Mol. Cell Biol. 24, 560–575 (2023).
pubmed: 36864290 doi: 10.1038/s41580-023-00585-z
Young, T. M. et al. Autophagy protects tumors from T cell-mediated cytotoxicity via inhibition of TNFα-induced apoptosis. Sci. Immunol. 5, eabb9561 (2020).
pubmed: 33443027 doi: 10.1126/sciimmunol.abb9561
Li, Z.-L. et al. Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation. Nat. Commun. 11, 3806 (2020).
pubmed: 32732922 pmcid: 7393512 doi: 10.1038/s41467-020-17395-y
Chryplewicz, A. et al. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity. Cancer Cell 40, 1111–1127.e9 (2022).
pubmed: 36113478 pmcid: 9580613 doi: 10.1016/j.ccell.2022.08.014
Chaib, S. et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat. Cancer 5, 448–462 (2024).
pubmed: 38267628 pmcid: 10965441 doi: 10.1038/s43018-023-00712-x
Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016). This study describes dichotomous roles of cancer cell senescence in liver cancer, in particular, the involvement of senescent cancer cells in suppressing NK cell-mediated killing.
pubmed: 27728804 pmcid: 7789819 doi: 10.1016/j.ccell.2016.09.003
Matsuda, S. et al. TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state. Cell Rep. 42, 112129 (2023). This study implicates hypoxia-induced TGFβ in driving the senescence of cancer cells, whose SASP recruits immunosuppressive immune cells, promoting immune evasion.
pubmed: 36821441 pmcid: 10187541 doi: 10.1016/j.celrep.2023.112129
Marzban, H. et al. Immunobiology of cancer stem cells and their immunoevasion mechanisms. Mol. Biol. Rep. 50, 9559–9573 (2023).
pubmed: 37776412 doi: 10.1007/s11033-023-08768-9
Li, L. & Jensen, R. A. Understanding and overcoming immunosuppression shaped by cancer stem cells. Cancer Res. 83, 2096–2104 (2023).
pubmed: 37403628 pmcid: 10320482 doi: 10.1158/0008-5472.CAN-23-0230
Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177, 1172–1186.e14 (2019).
pubmed: 31031009 pmcid: 6525024 doi: 10.1016/j.cell.2019.03.025
Luan, J. et al. CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment. Immunity 57, 1071–1086.e7 (2024).
pubmed: 38677291 doi: 10.1016/j.immuni.2024.04.003
Erickson, H. L. et al. Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors. Immunity 57, 1908–1922.e6 (2024).
pubmed: 39079535 doi: 10.1016/j.immuni.2024.07.004
Baldominos, P. et al. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell 185, 1694–1708.e19 (2022).
pubmed: 35447074 pmcid: 11332067 doi: 10.1016/j.cell.2022.03.033
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
pubmed: 21376230 doi: 10.1016/j.cell.2011.02.013
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
pubmed: 10647931 doi: 10.1016/S0092-8674(00)81683-9
De Palma, M. & Hanahan, D. Milestones in tumor vascularization and its therapeutic targeting. Nat. Cancer 5, 827–843 (2024).
pubmed: 38918437 doi: 10.1038/s43018-024-00780-7
Onrust, S. V., Hartl, P. M., Rosen, S. D. & Hanahan, D. Modulation of L-selectin ligand expression during an immune response accompanying tumorigenesis in transgenic mice. J. Clin. Invest. 97, 54–64 (1996). This study provides an early description of the development of the immunosuppressive TME in a genetically engineered mouse model of pancreatic neuroendocrine tumorigenesis, comparing inflamed pre-malignant lesions with uninflamed malignant tumours that lack HEVs.
pubmed: 8550850 pmcid: 507062 doi: 10.1172/JCI118406
Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 9, eaak9679 (2017). This study shows that the angiogenic tumour vasculature can be reprogrammed and quasi-normalized by VEGF pathway inhibitors to enable the induction of HEVs and productive antitumour immunity.
pubmed: 28404866 pmcid: 5554432 doi: 10.1126/scitranslmed.aak9679
Hosaka, K. et al. KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas. Proc. Natl Acad. Sci. USA 120, e2303740120 (2023).
pubmed: 37428914 pmcid: 10629547 doi: 10.1073/pnas.2303740120
Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).
pubmed: 8605350 doi: 10.1182/blood.V87.8.3336.bloodjournal8783336
Scholz, A. et al. Angiopoietin-2 promotes myeloid cell infiltration in a β
pubmed: 21868579 doi: 10.1182/blood-2011-03-343293
Kashyap, A. S. et al. Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy. Proc. Natl Acad. Sci. USA 117, 541–551 (2020). This study illustrates the immunological benefits of co-targeting VEGF and ANG2 signalling in the tumour vasculature, including the reprogramming of TAMs and the restoration of functionality in TADCs.
pubmed: 31889004 doi: 10.1073/pnas.1902145116
Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9, eaak9670 (2017). Functional validation with a bispecific blocking antibody shows the benefits of co-targeting VEGF and ANG2 signalling in the angiogenic vasculature across multiple mouse models of cancer, facilitating T cell extravasation and enhancing antitumour immunity.
pubmed: 28404865 doi: 10.1126/scitranslmed.aak9670
Amersfoort, J., Eelen, G. & Carmeliet, P. Immunomodulation by endothelial cells — partnering up with the immune system? Nat. Rev. Immunol. 22, 576–588 (2022).
pubmed: 35288707 pmcid: 8920067 doi: 10.1038/s41577-022-00694-4
Vella, G., Hua, Y. & Bergers, G. High endothelial venules in cancer: regulation, function, and therapeutic implication. Cancer Cell 41, 527–545 (2023).
pubmed: 36827979 doi: 10.1016/j.ccell.2023.02.002
Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P. & Griffioen, A. W. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540 (2021).
pubmed: 33833434 doi: 10.1038/s41571-021-00496-y
Verhoeven, J. et al. Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma. EMBO Mol. Med. 15, e18028 (2023).
pubmed: 38009521 pmcid: 10701618 doi: 10.15252/emmm.202318028
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
pubmed: 22439926 doi: 10.1016/j.ccr.2012.02.022
Viúdez-Pareja, C., Kreft, E. & García-Caballero, M. Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment. Front. Immunol. 14, 1235812 (2023).
pubmed: 37744339 pmcid: 10512957 doi: 10.3389/fimmu.2023.1235812
Karakousi, T., Mudianto, T. & Lund, A. W. Lymphatic vessels in the age of cancer immunotherapy. Nat. Rev. Cancer 24, 363–381 (2024).
pubmed: 38605228 doi: 10.1038/s41568-024-00681-y
Kataru, R. P. et al. Tumor lymphatic function regulates tumor inflammatory and immunosuppressive microenvironments. Cancer Immunol. Res. 7, 1345–1358 (2019).
pubmed: 31186247 pmcid: 6677612 doi: 10.1158/2326-6066.CIR-18-0337
Lund, A. W. et al. Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J. Clin. Invest. 126, 3389–3402 (2016).
pubmed: 27525437 pmcid: 5004967 doi: 10.1172/JCI79434
Dieterich, L. C. et al. Tumor-associated lymphatic vessels upregulate PDL1 to inhibit T-cell activation. Front. Immunol. 8, 66 (2017).
pubmed: 28217128 pmcid: 5289955 doi: 10.3389/fimmu.2017.00066
Dabravolski, S. A. et al. The role of pericytes in regulation of innate and adaptive immunity. Biomedicines 11, 600 (2023).
pubmed: 36831136 pmcid: 9953719 doi: 10.3390/biomedicines11020600
Valdor, R. et al. Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells. Oncotarget 8, 68614–68626 (2017).
pubmed: 28978142 pmcid: 5620282 doi: 10.18632/oncotarget.19804
Valdor, R. et al. Glioblastoma ablates pericytes antitumor immune function through aberrant up-regulation of chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 116, 20655–20665 (2019). This is an intriguing study, yet to be generalized, that describes an immunosuppressive programme induced in pericytes in glioblastoma.
pubmed: 31548426 pmcid: 6789971 doi: 10.1073/pnas.1903542116
Braun, S. et al. Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma. Preprint at bioRxiv https://doi.org/10.1101/2024.08.26.609765 (2024).
Kim, I., Choi, S., Yoo, S., Lee, M. & Kim, I.-S. Cancer-associated fibroblasts in the hypoxic tumor microenvironment. Cancers 14, 3321 (2022).
pubmed: 35884382 pmcid: 9320406 doi: 10.3390/cancers14143321
Kennel, K. B., Bozlar, M., De Valk, A. F. & Greten, F. R. Cancer-associated fibroblasts in inflammation and antitumor immunity. Clin. Cancer Res. 29, 1009–1016 (2023).
pubmed: 36399325 doi: 10.1158/1078-0432.CCR-22-1031
Cords, L. et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer. Cancer Cell 42, 396–412.e5 (2024).
pubmed: 38242124 pmcid: 10929690 doi: 10.1016/j.ccell.2023.12.021
Luo, H. et al. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment. Nat. Commun. 13, 6619 (2022). This study uses single-cell RNA sequencing to characterize CAF subtypes, cell states and phenotypic plasticity across ten cancer types.
pubmed: 36333338 pmcid: 9636408 doi: 10.1038/s41467-022-34395-2
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
pubmed: 31980749 pmcid: 7046529 doi: 10.1038/s41568-019-0238-1
Croizer, H. et al. Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer. Nat. Commun. 15, 2806 (2024).
pubmed: 38561380 pmcid: 10984943 doi: 10.1038/s41467-024-47068-z
Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017). This study delineates CAF subtypes and phenotypes in mouse and human PDAC.
pubmed: 28232471 pmcid: 5339682 doi: 10.1084/jem.20162024
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
pubmed: 31197017 pmcid: 6727976 doi: 10.1158/2159-8290.CD-19-0094
Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).
pubmed: 30514914 pmcid: 6279758 doi: 10.1038/s41467-018-07582-3
Milosevic, V. & Östman, A. Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential. Ups J. Med. Sci. 129, e10710 (2024).
doi: 10.48101/ujms.v129.10710
Yang, D., Liu, J., Qian, H. & Zhuang, Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp. Mol. Med. 55, 1322–1332 (2023).
pubmed: 37394578 pmcid: 10394065 doi: 10.1038/s12276-023-01013-0
Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15
pubmed: 31699795 doi: 10.1158/2159-8290.CD-19-0644
Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).
pubmed: 32434947 doi: 10.1158/2159-8290.CD-19-1384
Krishnamurty, A. T. et al. LRRC15
pubmed: 36171287 pmcid: 9630141 doi: 10.1038/s41586-022-05272-1
Belle, J. I. et al. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov. 14, 1324–1355 (2024). This study describes and functionally validates senescent myCAFs as potent instigators of T cell immunosuppression in a mouse model of pancreatic cancer, with evidence of their presence in human tumours as well.
pubmed: 38683144 doi: 10.1158/2159-8290.CD-23-0428
Kuczek, D. E. et al. Collagen density regulates the activity of tumor-infiltrating T cells. J. Immunother. Cancer 7, 68 (2019).
pubmed: 30867051 pmcid: 6417085 doi: 10.1186/s40425-019-0556-6
Caligiuri, G. & Tuveson, D. A. Activated fibroblasts in cancer: perspectives and challenges. Cancer Cell 41, 434–449 (2023).
pubmed: 36917949 pmcid: 11022589 doi: 10.1016/j.ccell.2023.02.015
Gao, H. et al. 3D extracellular matrix regulates the activity of T cells and cancer associated fibroblasts in breast cancer. Front. Oncol. 11, 764204 (2021). This study demonstrates how elevated ECM density enhances CAF abundance and activity while reducing T cell infiltration in mouse models of breast cancer, with similar associations observed in human breast cancer.
pubmed: 34956886 pmcid: 8699235 doi: 10.3389/fonc.2021.764204
Tharp, K. M. et al. Tumor-associated macrophages restrict CD8
pubmed: 38831058 doi: 10.1038/s43018-024-00775-4
Tran, L. L., Dang, T., Thomas, R. & Rowley, D. R. ELF3 mediates IL-1α induced differentiation of mesenchymal stem cells to inflammatory iCAFs. Stem Cell 39, 1766–1777 (2021).
doi: 10.1002/stem.3455
Li, T. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 318, 154–161 (2012).
pubmed: 22182446 doi: 10.1016/j.canlet.2011.12.020
Gok Yavuz, B. et al. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1
pubmed: 30816272 pmcid: 6395633 doi: 10.1038/s41598-019-39553-z
Biffi, G. et al. IL1-Induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).
pubmed: 30366930 doi: 10.1158/2159-8290.CD-18-0710
Chen, H. et al. Integrated analysis revealed an inflammatory cancer-associated fibroblast-based subtypes with promising implications in predicting the prognosis and immunotherapeutic response of bladder cancer patients. Int. J. Mol. Sci. 23, 15970 (2022).
pubmed: 36555612 pmcid: 9781727 doi: 10.3390/ijms232415970
Nicolas, A. M. et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell 40, 168–184.e13 (2022).
pubmed: 35120600 doi: 10.1016/j.ccell.2022.01.004
Cassetta, L. & Pollard, J. W. A timeline of tumour-associated macrophage biology. Nat. Rev. Cancer 23, 238–257 (2023).
pubmed: 36792751 doi: 10.1038/s41568-022-00547-1
Kloosterman, D. J. & Akkari, L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell 186, 1627–1651 (2023).
pubmed: 36924769 doi: 10.1016/j.cell.2023.02.020
Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016).
pubmed: 27339708 doi: 10.1038/nrc.2016.54
Steidl, C. et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N. Engl. J. Med. 362, 875–885 (2010).
pubmed: 20220182 pmcid: 2897174 doi: 10.1056/NEJMoa0905680
Zhang, Q. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE 7, e50946 (2012).
pubmed: 23284651 pmcid: 3532403 doi: 10.1371/journal.pone.0050946
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
pubmed: 26193342 pmcid: 4852857 doi: 10.1038/nm.3909
Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF
pubmed: 29191879 pmcid: 6343476 doi: 10.1126/science.aal5081
Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).
pubmed: 23221383 doi: 10.1158/0008-5472.CAN-12-2731
Kersten, K. et al. Spatiotemporal co-dependency between macrophages and exhausted CD8
pubmed: 35623342 pmcid: 9197962 doi: 10.1016/j.ccell.2022.05.004
Deng, Z. et al. The nuclear factor ID3 endows macrophages with a potent anti-tumour activity. Nature 626, 864–873 (2024).
pubmed: 38326607 pmcid: 10881399 doi: 10.1038/s41586-023-06950-4
Pucci, F. et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352, 242–246 (2016).
pubmed: 26989197 pmcid: 4960636 doi: 10.1126/science.aaf1328
Nalio Ramos, R. et al. Tissue-resident FOLR2
pubmed: 35325594 doi: 10.1016/j.cell.2022.02.021
Hirschhorn, D. et al. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell 186, 1432–1447.e17 (2023).
pubmed: 37001503 pmcid: 10994488 doi: 10.1016/j.cell.2023.03.007
Gungabeesoon, J. et al. A neutrophil response linked to tumor control in immunotherapy. Cell 186, 1448–1464.e20 (2023).
pubmed: 37001504 pmcid: 10132778 doi: 10.1016/j.cell.2023.02.032
Benguigui, M. et al. Interferon-stimulated neutrophils as a predictor of immunotherapy response. Cancer Cell 42, 253–265.e12 (2024).
pubmed: 38181798 pmcid: 10864002 doi: 10.1016/j.ccell.2023.12.005
Quail, D. F. et al. Neutrophil phenotypes and functions in cancer: a consensus statement. J. Exp. Med. 219, e20220011 (2022).
pubmed: 35522219 pmcid: 9086501 doi: 10.1084/jem.20220011
Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).
pubmed: 35354979 doi: 10.1038/s41571-022-00620-6
Pittet, M. J., Di Pilato, M., Garris, C. & Mempel, T. R. Dendritic cells as shepherds of T cell immunity in cancer. Immunity 56, 2218–2230 (2023).
pubmed: 37708889 pmcid: 10591862 doi: 10.1016/j.immuni.2023.08.014
Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).
pubmed: 25446897 pmcid: 4254577 doi: 10.1016/j.ccell.2014.09.007
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). This seminal work shows how a genetic alteration in cancer cells prevents the accumulation of TADCs.
pubmed: 25970248 doi: 10.1038/nature14404
Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334.e10 (2019).
pubmed: 30979687 pmcid: 6620049 doi: 10.1016/j.immuni.2019.03.009
MacNabb, B. W. et al. Dendritic cells can prime anti-tumor CD8
pubmed: 35617964 pmcid: 9883788 doi: 10.1016/j.immuni.2022.04.016
Garris, C. S. et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity 49, 1148–1161.e7 (2018).
pubmed: 30552023 pmcid: 6301092 doi: 10.1016/j.immuni.2018.09.024
Di Pilato, M. et al. CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell 184, 4512–4530.e22 (2021).
pubmed: 34343496 pmcid: 8719451 doi: 10.1016/j.cell.2021.07.015
Klemm, F. et al. Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis. Nat. Cancer 2, 1086–1101 (2021).
pubmed: 35121879 doi: 10.1038/s43018-021-00254-0
Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
pubmed: 24056773 pmcid: 3840724 doi: 10.1038/nm.3337
Neubert, N. J. et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl. Med. 10, eaan3311 (2018). This work shows that CD8
pubmed: 29643229 pmcid: 5957531 doi: 10.1126/scitranslmed.aan3311
Cortez-Retamozo, V. et al. Angiotensin II drives the production of tumor-promoting macrophages. Immunity 38, 296–308 (2013).
pubmed: 23333075 pmcid: 3582771 doi: 10.1016/j.immuni.2012.10.015
Di Conza, G. et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nat. Immunol. 22, 1403–1415 (2021).
pubmed: 34686867 pmcid: 7611917 doi: 10.1038/s41590-021-01047-4
Zhang, B. et al. B cell-derived GABA elicits IL-10
pubmed: 34732892 pmcid: 8599023 doi: 10.1038/s41586-021-04082-1
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).
pubmed: 31645732 pmcid: 6818755 doi: 10.1038/s41586-019-1678-1
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
pubmed: 25043024 pmcid: 4301845 doi: 10.1038/nature13490
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
pubmed: 20141834 pmcid: 2836922 doi: 10.1016/j.cell.2009.12.052
Caronni, N. et al. IL-1β
pubmed: 37914939 doi: 10.1038/s41586-023-06685-2
Wu, J.-Y. et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol. Cell 77, 213–227.e5 (2020).
pubmed: 31735641 doi: 10.1016/j.molcel.2019.10.023
Bill, R. et al. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science 381, 515–524 (2023). This work reveals that the polarity of TAMs, as defined by the expression of CXCL9 and SPP1, is a critical feature of TMEs and is tightly linked to T cell activity.
pubmed: 37535729 pmcid: 10755760 doi: 10.1126/science.ade2292
Bader, J. E. et al. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity. Nature 630, 968–975 (2024).
pubmed: 38867043 doi: 10.1038/s41586-024-07529-3
Wang, X. et al. In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target. Cell 184, 5357–5374.e22 (2021).
pubmed: 34582788 pmcid: 9136996 doi: 10.1016/j.cell.2021.09.006
Guan, W. et al. Tumor-associated macrophage promotes the survival of cancer cells upon docetaxel chemotherapy via the CSF1/CSF1R-CXCL12/CXCR4 axis in castration-resistant prostate cancer. Genes 12, 773 (2021).
pubmed: 34069563 pmcid: 8161256 doi: 10.3390/genes12050773
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
pubmed: 22039576 pmcid: 3203524 doi: 10.1158/2159-8274.CD-10-0028
Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).
pubmed: 26269531 pmcid: 5024531 doi: 10.1158/0008-5472.CAN-14-3587
Walens, A. et al. CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors. eLife 8, e43653 (2019).
pubmed: 30990165 pmcid: 6478432 doi: 10.7554/eLife.43653
Mantovani, A., Allavena, P., Marchesi, F. & Garlanda, C. Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug Discov. 21, 799–820 (2022).
pubmed: 35974096 pmcid: 9380983 doi: 10.1038/s41573-022-00520-5
Tichet, M. et al. Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8
pubmed: 36630914 doi: 10.1016/j.immuni.2022.12.006
Kuang, D.-M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).
pubmed: 19451266 pmcid: 2715058 doi: 10.1084/jem.20082173
Chang, C.-H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
pubmed: 26321679 pmcid: 4864363 doi: 10.1016/j.cell.2015.08.016
Pfirschke, C. et al. Macrophage-targeted therapy unlocks antitumoral cross-talk between IFNγ-secreting lymphocytes and IL12-producing dendritic cells. Cancer Immunol. Res. 10, 40–55 (2022).
pubmed: 34795032 doi: 10.1158/2326-6066.CIR-21-0326
Ruffell, B. et al. Macrophage IL-10 blocks CD8
pubmed: 25446896 pmcid: 4254570 doi: 10.1016/j.ccell.2014.09.006
Matusiak, M. et al. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov. 14, 1418–1439 (2024).
pubmed: 38552005 pmcid: 11294822 doi: 10.1158/2159-8290.CD-23-1300
Bianchi, A. et al. Cell-autonomous Cxcl1 sustains tolerogenic circuitries and stromal inflammation via neutrophil-derived TNF in pancreatic cancer. Cancer Discov. 13, 1428–1453 (2023).
pubmed: 36946782 pmcid: 10259764 doi: 10.1158/2159-8290.CD-22-1046
Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019).
pubmed: 31367040 pmcid: 6707815 doi: 10.1038/s41586-019-1450-6
Gong, Z. et al. Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis. Sci. Immunol. 8, eadd5204 (2023).
pubmed: 36800412 pmcid: 10067025 doi: 10.1126/sciimmunol.add5204
Zhao, J. et al. Tumor-specific neutrophils originating from meninges promote glioblastoma. Preprint at bioRxiv https://doi.org/10.1101/2023.05.23.542010 (2023).
Simoncello, F. et al. CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors. Oncoimmunology 11, 2059876 (2022).
pubmed: 35402081 pmcid: 8993093 doi: 10.1080/2162402X.2022.2059876
Sanmamed, M. F. et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin. Cancer Res. 20, 5697–5707 (2014).
pubmed: 25224278 doi: 10.1158/1078-0432.CCR-13-3203
Alfaro, C. et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin. Cancer Res. 22, 3924–3936 (2016).
pubmed: 26957562 doi: 10.1158/1078-0432.CCR-15-2463
Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).
pubmed: 27265504 pmcid: 4912354 doi: 10.1016/j.ccell.2016.04.014
Guo, C. et al. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Nature 623, 1053–1061 (2023). This work shows that inhibiting CXCR2 in patients with prostate cancer not only limits neutrophil accumulation in tumours but also has therapeutic effects.
pubmed: 37844613 pmcid: 10686834 doi: 10.1038/s41586-023-06696-z
Bezzi, M. et al. Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms. Nat. Med. 24, 165–175 (2018).
pubmed: 29309058 doi: 10.1038/nm.4463
Bodac, A. et al. Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. EMBO Mol. Med. 16, 158–184 (2024).
pubmed: 38177532 doi: 10.1038/s44321-023-00013-x
Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G
pubmed: 21081700 pmcid: 3003076 doi: 10.1073/pnas.1015855107
Bronte, V. et al. Unopposed production of granulocyte–macrophage colony-stimulating factor by tumors inhibits CD8
pubmed: 10229805 doi: 10.4049/jimmunol.162.10.5728
Kohanbash, G. et al. GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-α. Cancer Res. 73, 6413–6423 (2013).
pubmed: 24030977 doi: 10.1158/0008-5472.CAN-12-4124
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: ‘N1’ versus ‘N2’ TAN. Cancer Cell 16, 183–194 (2009).
pubmed: 19732719 pmcid: 2754404 doi: 10.1016/j.ccr.2009.06.017
Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015). This work shows that tumours can promote metastasis through a systemic inflammatory cascade involving neutrophils that suppress antitumour CD8
pubmed: 25822788 pmcid: 4475637 doi: 10.1038/nature14282
Maas, R. R. et al. The local microenvironment drives activation of neutrophils in human brain tumors. Cell 186, 4546–4566.e27 (2023).
pubmed: 37769657 doi: 10.1016/j.cell.2023.08.043
Bell, C. R. et al. Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations. Nat. Commun. 13, 2063 (2022).
pubmed: 35440553 pmcid: 9018752 doi: 10.1038/s41467-022-29606-9
Bancaro, N. et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell 41, 602–619.e11 (2023).
pubmed: 36868226 doi: 10.1016/j.ccell.2023.02.004
McDowell, S. A. C. et al. Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration. Nat. Cancer 2, 545–562 (2021).
pubmed: 35122017 doi: 10.1038/s43018-021-00194-9
Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).
pubmed: 26759232 pmcid: 4794393 doi: 10.1158/0008-5472.CAN-15-1591
Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).
pubmed: 30262472 pmcid: 6777850 doi: 10.1126/science.aao4227
Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).
pubmed: 26649828 pmcid: 4700594 doi: 10.1038/nature16140
Enfield, K. S. S. et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer. Cancer Discov. 14, 1018–1047 (2024).
pubmed: 38581685 pmcid: 11145179 doi: 10.1158/2159-8290.CD-23-1380
Siwicki, M. & Pittet, M. J. Versatile neutrophil functions in cancer. Semin. Immunol. 57, 101538 (2021).
pubmed: 34876331 doi: 10.1016/j.smim.2021.101538
Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022). This work shows that ferroptosis in neutrophils suppresses antitumour immunity.
pubmed: 36385526 pmcid: 9875862 doi: 10.1038/s41586-022-05443-0
Mousset, A. et al. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation. Cancer Cell 41, 757–775.e10 (2023).
pubmed: 37037615 pmcid: 10228050 doi: 10.1016/j.ccell.2023.03.008
He, X.-Y. et al. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell 42, 474–486.e12 (2024).
pubmed: 38402610 doi: 10.1016/j.ccell.2024.01.013
Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).
pubmed: 16891410 pmcid: 1531646 doi: 10.1073/pnas.0601807103
Vijver, S. V. et al. Collagen fragments produced in cancer mediate T cell suppression through leukocyte-associated immunoglobulin-like receptor 1. Front. Immunol. 12, 733561 (2021).
pubmed: 34691040 pmcid: 8529287 doi: 10.3389/fimmu.2021.733561
Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020). This work shows that a population of TADCs involved in antitumour T cell immunity can be suppressed by IL-4 signalling.
pubmed: 32269339 pmcid: 7787191 doi: 10.1038/s41586-020-2134-y
Kim, S. et al. IL-6 selectively suppresses cDC1 specification via C/EBPβ. J. Exp. Med. 220, e20221757 (2023).
pubmed: 37432392 pmcid: 10336151 doi: 10.1084/jem.20221757
Kobie, J. J. et al. Transforming growth factor β inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res. 63, 1860–1864 (2003).
pubmed: 12702574
Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1124 (2008).
pubmed: 18193223 pmcid: 4110970 doi: 10.1007/s00262-007-0441-x
Bayerl, F. et al. Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses. Immunity 56, 1341–1358.e11 (2023). This work shows how PGE
pubmed: 37315536 doi: 10.1016/j.immuni.2023.05.011
Veglia, F. et al. Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nat. Commun. 8, 2122 (2017).
pubmed: 29242535 pmcid: 5730553 doi: 10.1038/s41467-017-02186-9
Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic. Cell Homeost. Cell 161, 1527–1538 (2015).
Laumont, C. M., Banville, A. C., Gilardi, M., Hollern, D. P. & Nelson, B. H. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat. Rev. Cancer 22, 414–430 (2022).
pubmed: 35393541 pmcid: 9678336 doi: 10.1038/s41568-022-00466-1
Bruni, D., Angell, H. K. & Galon, J. The immune contexture and immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).
pubmed: 32753728 doi: 10.1038/s41568-020-0285-7
Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).
pubmed: 31942071 doi: 10.1038/s41586-019-1914-8
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).
pubmed: 31942075 pmcid: 8762581 doi: 10.1038/s41586-019-1922-8
Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).
pubmed: 31942077 doi: 10.1038/s41586-019-1906-8
Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25
pubmed: 10553041 doi: 10.4049/jimmunol.163.10.5211
Onizuka, S. et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res. 59, 3128–3133 (1999).
pubmed: 10397255
Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S. & Bhan, A. K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219–230 (2002).
pubmed: 11869683 doi: 10.1016/S1074-7613(02)00274-1
Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).
pubmed: 30705439 doi: 10.1038/s41571-019-0175-7
Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a T
pubmed: 26411680 pmcid: 5013825 doi: 10.1016/j.celrep.2015.08.077
Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498–1512.e5 (2019).
pubmed: 31097342 pmcid: 6527362 doi: 10.1016/j.immuni.2019.04.010
Moreno Ayala, M. A. et al. CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8
pubmed: 37392735 doi: 10.1016/j.immuni.2023.06.003
Spranger, S. et al. Up-regulation of PD-L1, IDO, and T
pubmed: 23986400 pmcid: 4136707 doi: 10.1126/scitranslmed.3006504
Martinez-Usatorre, A. et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci. Transl. Med. 13, eabd1616 (2021).
pubmed: 34380768 pmcid: 7612153 doi: 10.1126/scitranslmed.abd1616
Kamada, T. et al. PD-1
pubmed: 31028147 pmcid: 6525547 doi: 10.1073/pnas.1822001116
Fidelle, M. et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science 380, eabo2296 (2023).
pubmed: 37289890 doi: 10.1126/science.abo2296
Chen, M.-L. et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc. Natl Acad. Sci. USA 102, 419–424 (2005).
pubmed: 15623559 doi: 10.1073/pnas.0408197102
Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).
pubmed: 16860762 doi: 10.1016/j.immuni.2006.04.015
Turnis, M. E. et al. Interleukin-35 limits anti-tumor immunity. Immunity 44, 316–329 (2016).
pubmed: 26872697 pmcid: 4758699 doi: 10.1016/j.immuni.2016.01.013
Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
pubmed: 18033300 doi: 10.1038/nature06306
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
pubmed: 17502665 pmcid: 2118603 doi: 10.1084/jem.20062512
Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).
pubmed: 15485635 doi: 10.1016/j.immuni.2004.09.002
Wing, K. et al. CTLA-4 control over Foxp3
pubmed: 18845758 doi: 10.1126/science.1160062
Marangoni, F. et al. Expansion of tumor-associated T
pubmed: 34157302 pmcid: 8664158 doi: 10.1016/j.cell.2021.05.027
Mishima, Y. et al. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J. Clin. Invest. 129, 3702–3716 (2019).
pubmed: 31211700 pmcid: 6715367 doi: 10.1172/JCI93820
Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).
pubmed: 24572363 pmcid: 4260166 doi: 10.1038/nature12979
Yoshizaki, A. et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012).
pubmed: 23064231 pmcid: 3493692 doi: 10.1038/nature11501
Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).
pubmed: 25326801 doi: 10.1038/nm.3680
Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).
pubmed: 20138013 pmcid: 3082507 doi: 10.1016/j.ccr.2009.12.019
Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).
pubmed: 24909985 pmcid: 4063283 doi: 10.1016/j.ccr.2014.04.026
Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4
pubmed: 21444674 pmcid: 3096701 doi: 10.1158/0008-5472.CAN-10-4316
Horikawa, M., Minard-Colin, V., Matsushita, T. & Tedder, T. F. Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J. Clin. Invest. 121, 4268–4280 (2011).
pubmed: 22019587 pmcid: 3204847 doi: 10.1172/JCI59266
Xiao, X. et al. PD-1
pubmed: 26928313 doi: 10.1158/2159-8290.CD-15-1408
Pylayeva-Gupta, Y. et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016).
pubmed: 26715643 doi: 10.1158/2159-8290.CD-15-0843
Ammirante, M., Luo, J.-L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).
pubmed: 20220849 pmcid: 2866639 doi: 10.1038/nature08782
Bod, L. et al. B-cell-specific checkpoint molecules that regulate anti-tumour immunity. Nature 619, 348–356 (2023).
pubmed: 37344597 pmcid: 10795478 doi: 10.1038/s41586-023-06231-0
Ruf, B., Greten, T. F. & Korangy, F. Innate lymphoid cells and innate-like T cells in cancer — at the crossroads of innate and adaptive immunity. Nat. Rev. Cancer 23, 351–371 (2023).
pubmed: 37081117 doi: 10.1038/s41568-023-00562-w
Corvino, D., Kumar, A. & Bald, T. Plasticity of NK cells in cancer. Front. Immunol. 13, 888313 (2022).
pubmed: 35619715 pmcid: 9127295 doi: 10.3389/fimmu.2022.888313
Portale, F. & Di Mitri, D. NK cells in cancer: mechanisms of dysfunction and therapeutic potential. Int. J. Mol. Sci. 24, 9521 (2023).
pubmed: 37298470 pmcid: 10253405 doi: 10.3390/ijms24119521
Tong, L. et al. NK cells and solid tumors: therapeutic potential and persisting obstacles. Mol. Cancer 21, 206 (2022).
pubmed: 36319998 pmcid: 9623927 doi: 10.1186/s12943-022-01672-z
Chung, D. C. et al. Generation of an inhibitory NK cell subset by TGF-β1/IL-15 polarization. J. Immunol. 212, 1904–1912 (2024).
pubmed: 38668728 pmcid: 11149900 doi: 10.4049/jimmunol.2300834
Boonpiyathad, T., Sözener, Z. C., Satitsuksanoa, P. & Akdis, C. A. Immunologic mechanisms in asthma. Semin. Immunol. 46, 101333 (2019).
pubmed: 31703832 doi: 10.1016/j.smim.2019.101333
Ercolano, G., Falquet, M., Vanoni, G., Trabanelli, S. & Jandus, C. ILC2s: new actors in tumor immunity. Front. Immunol. 10, 2801 (2019).
pubmed: 31849977 pmcid: 6902088 doi: 10.3389/fimmu.2019.02801
Panda, S. K. & Colonna, M. Innate lymphoid cells in mucosal immunity. Front. Immunol. 10, 861 (2019).
pubmed: 31134050 pmcid: 6515929 doi: 10.3389/fimmu.2019.00861
Carrega, P. et al. NCR
pubmed: 26395069 doi: 10.1038/ncomms9280
Eisenring, M., vom Berg, J., Kristiansen, G., Saller, E. & Becher, B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat. Immunol. 11, 1030–1038 (2010).
pubmed: 20935648 doi: 10.1038/ni.1947
Sonnenberg, G. F. & Hepworth, M. R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat. Rev. Immunol. 19, 599–613 (2019).
pubmed: 31350531 pmcid: 6982279 doi: 10.1038/s41577-019-0194-8
Wang, W. et al. Nerves in the tumor microenvironment: origin and effects. Front. Cell Dev. Biol. 8, 601738 (2020).
pubmed: 33392191 pmcid: 7773823 doi: 10.3389/fcell.2020.601738
Reavis, H. D., Chen, H. I. & Drapkin, R. Tumor innervation: cancer has some nerve. Trends Cancer 6, 1059–1067 (2020).
pubmed: 32807693 pmcid: 7688507 doi: 10.1016/j.trecan.2020.07.005
Hanahan, D. & Monje, M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell 41, 573–580 (2023).
pubmed: 36917953 pmcid: 10202656 doi: 10.1016/j.ccell.2023.02.012
Wrona, D. Neural–immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J. Neuroimmunol. 172, 38–58 (2006).
pubmed: 16375977 doi: 10.1016/j.jneuroim.2005.10.017
Anisman, H. et al. Neuroimmune mechanisms in health and disease: 1. Health. CMAJ 155, 867–874 (1996).
pubmed: 8837533 pmcid: 1335446
Eckerling, A., Ricon-Becker, I., Sorski, L., Sandbank, E. & Ben-Eliyahu, S. Stress and cancer: mechanisms, significance and future directions. Nat. Rev. Cancer 21, 767–785 (2021).
pubmed: 34508247 doi: 10.1038/s41568-021-00395-5
Bucsek, M. J. et al. β-Adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8
pubmed: 28819022 pmcid: 5645237 doi: 10.1158/0008-5472.CAN-17-0546
Qiao, G., Chen, M., Bucsek, M. J., Repasky, E. A. & Hylander, B. L. Adrenergic signaling: a targetable checkpoint limiting development of the antitumor immune response. Front. Immunol. 9, 164 (2018).
pubmed: 29479349 pmcid: 5812031 doi: 10.3389/fimmu.2018.00164
Globig, A.-M. et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383–392 (2023). Functional studies in mouse models document the T cell-inhibiting effects of stress-induced catecholamines released through sympathetic innervation of tumours, a correlation that translates in human association studies.
pubmed: 37731001 pmcid: 10871066 doi: 10.1038/s41586-023-06568-6
Haldar, R. et al. Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: a randomized controlled trial. Cancer 126, 3991–4001 (2020).
pubmed: 32533792 doi: 10.1002/cncr.32950
Yang, M.-W. et al. Perineural invasion reprograms the immune microenvironment through cholinergic signaling in pancreatic ductal adenocarcinoma. Cancer Res. 80, 1991–2003 (2020). This study demonstrates that acetylcholine released from parasympathetic neurons in the context of perineural invasion by cancer cells is immunosuppressive, acting on both cancer cells and T cells.
pubmed: 32098780 doi: 10.1158/0008-5472.CAN-19-2689
Guo, X. et al. Midkine activation of CD8
pubmed: 32358581 pmcid: 7195398 doi: 10.1038/s41467-020-15770-3
Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024).
pubmed: 38552609 doi: 10.1016/j.cell.2024.02.009
Derosa, L. et al. Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome. Cell 187, 3373–3389.e16 (2024).
pubmed: 38906102 doi: 10.1016/j.cell.2024.05.029
Wu, J., Zhang, P., Mei, W. & Zeng, C. Intratumoral microbiota: implications for cancer onset, progression, and therapy. Front. Immunol. 14, 1301506 (2023).
pubmed: 38292482 doi: 10.3389/fimmu.2023.1301506
Guan, S.-W., Lin, Q. & Yu, H.-B. Intratumour microbiome of pancreatic cancer. World J. Gastrointest. Oncol. 15, 713–730 (2023).
pubmed: 37275446 pmcid: 10237023 doi: 10.4251/wjgo.v15.i5.713
Falcomatà, C. et al. Context-specific determinants of the immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Discov. 13, 278–297 (2023).
pubmed: 36622087 pmcid: 9900325 doi: 10.1158/2159-8290.CD-22-0876
Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018). This study delineates bacteria selectively abundant in pancreatic tumours compared with the gut, which are functionally involved in suppressing adaptive antitumour immunity, implicating the tumour microbiome as an immunomodulatory component of the TME.
pubmed: 29567829 pmcid: 6225783 doi: 10.1158/2159-8290.CD-17-1134
Chen, Y. et al. Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer. Cancer Cell 40, 818–834.e9 (2022). This study describes the functional activity of a collagen homotrimer expressed by pancreatic cancer cells, which modulates the immunosuppressive phenotype of the tumour microbiome.
pubmed: 35868307 pmcid: 9831277 doi: 10.1016/j.ccell.2022.06.011
Goubet, A.-G. Could the tumor-associated microbiota be the new multi-faceted player in the tumor microenvironment? Front. Oncol. 13, 1185163 (2023).
pubmed: 37287916 pmcid: 10242102 doi: 10.3389/fonc.2023.1185163
Gihawi, A. et al. Major data analysis errors invalidate cancer microbiome findings. mBio 14, e0160723 (2023).
pubmed: 37811944 doi: 10.1128/mbio.01607-23
Gihawi, A., Cooper, C. S. & Brewer, D. S. Caution regarding the specificities of pan-cancer microbial structure. Microb. Genom. 9, mgen001088 (2023).
pubmed: 37555750 pmcid: 10483429
Luo, Z. et al. Modulating tumor physical microenvironment for fueling CAR-T cell therapy. Adv. Drug. Deliv. Rev. 185, 114301 (2022).
pubmed: 35439570 doi: 10.1016/j.addr.2022.114301
Nia, H. T., Munn, L. L. & Jain, R. K. Physical traits of cancer. Science 370, eaaz0868 (2020).
pubmed: 33122355 pmcid: 8274378 doi: 10.1126/science.aaz0868
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
pubmed: 24856585 pmcid: 4096698 doi: 10.1016/j.ccr.2014.04.021
Piersma, B., Hayward, M.-K. & Weaver, V. M. Fibrosis and cancer: a strained relationship. Biochim. Biophys. Acta Rev. Cancer 1873, 188356 (2020).
pubmed: 32147542 pmcid: 7733542 doi: 10.1016/j.bbcan.2020.188356
Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).
pubmed: 24856586 pmcid: 4180632 doi: 10.1016/j.ccr.2014.04.005
Menjivar, R. E. et al. Arginase 1 is a key driver of immune suppression in pancreatic cancer. eLife 12, e80721 (2023).
pubmed: 36727849 pmcid: 10260021 doi: 10.7554/eLife.80721
Perricone, M. D. & Lyssiotis, C. A. Fibrotic tumors tune metabolism for immune evasion. Nat. Cancer 5, 955–957 (2024).
pubmed: 38831057 doi: 10.1038/s43018-024-00758-5
Arner, E. N. & Rathmell, J. C. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell 41, 421–433 (2023).
pubmed: 36801000 pmcid: 10023409 doi: 10.1016/j.ccell.2023.01.009
Siska, P. J. et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2, e93411 (2017).
pubmed: 28614802 pmcid: 5470888 doi: 10.1172/jci.insight.93411
Jiang, H., Hegde, S. & DeNardo, D. G. Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy. Cancer Immunol. Immunother. 66, 1037–1048 (2017).
pubmed: 28451791 pmcid: 5603233 doi: 10.1007/s00262-017-2003-1
Hiam-Galvez, K. J., Allen, B. M. & Spitzer, M. H. Systemic immunity in cancer. Nat. Rev. Cancer 21, 345–359 (2021).
pubmed: 33837297 pmcid: 8034277 doi: 10.1038/s41568-021-00347-z
Galliverti, G. et al. Myeloid cells orchestrate systemic immunosuppression, impairing the efficacy of immunotherapy against HPV
pubmed: 31771984 doi: 10.1158/2326-6066.CIR-19-0315
Allen, B. M. et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat. Med. 26, 1125–1134 (2020). Together with Galliverti et al. (2020), this study describes a new facet of immune evasion, namely, the capability of certain cancer cells in several mouse models to systemically suppress the generation and expansion of tumour-specific T cells in the lymphatic organs.
pubmed: 32451499 pmcid: 7384250 doi: 10.1038/s41591-020-0892-6
Biswas, A. K. & Acharyya, S. Understanding cachexia in the context of metastatic progression. Nat. Rev. Cancer 20, 274–284 (2020).
pubmed: 32235902 doi: 10.1038/s41568-020-0251-4
Nakamura, Y., Saldajeno, D. P., Kawaguchi, K. & Kawaoka, S. Progressive, multi-organ, and multi-layered nature of cancer cachexia. Cancer Sci. 115, 715–722 (2024).
pubmed: 38254286 pmcid: 10921013 doi: 10.1111/cas.16078
Ferreira, C. S. et al. Predictive potential of angiopoietin-2 in a mCRC subpopulation treated with vanucizumab in the McCAVE trial. Front. Oncol. 13, 1157596 (2023).
pubmed: 37207143 pmcid: 10190963 doi: 10.3389/fonc.2023.1157596
Albain, K. S. et al. Neoadjuvant trebananib plus paclitaxel-based chemotherapy for stage II/III breast cancer in the adaptively randomized I-SPY2 trial-efficacy and biomarker discovery. Clin. Cancer Res. 30, 729–740 (2024).
pubmed: 38109213 pmcid: 10956403 doi: 10.1158/1078-0432.CCR-22-2256
Bilen, M. A. et al. Association of neutrophil-to-lymphocyte ratio with efficacy of first-line avelumab plus axitinib vs. sunitinib in patients with advanced renal cell carcinoma enrolled in the phase 3 JAVELIN renal 101 trial. Clin. Cancer Res. 28, 738–747 (2022).
pubmed: 34789480 doi: 10.1158/1078-0432.CCR-21-1688
Kuo, H.-Y., Khan, K. A. & Kerbel, R. S. Antiangiogenic-immune-checkpoint inhibitor combinations: lessons from phase III clinical trials. Nat. Rev. Clin. Oncol. 21, 468–482 (2024).
pubmed: 38600370 doi: 10.1038/s41571-024-00886-y
Binnewies, M. et al. Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell Rep. 37, 109844 (2021). This article illustrates the potential for therapeutic targeting of immunosuppressive TAMs to enhance antitumour immunity.
pubmed: 34686340 doi: 10.1016/j.celrep.2021.109844
Kaczanowska, S. et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell 184, 2033–2052.e21 (2021).
pubmed: 33765443 pmcid: 8344805 doi: 10.1016/j.cell.2021.02.048
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).
pubmed: 32361713 pmcid: 7883632 doi: 10.1038/s41587-020-0462-y
Mund, A., Brunner, A.-D. & Mann, M. Unbiased spatial proteomics with single-cell resolution in tissues. Mol. Cell 82, 2335–2349 (2022).
pubmed: 35714588 doi: 10.1016/j.molcel.2022.05.022
Jin, Y. et al. Advances in spatial transcriptomics and its applications in cancer research. Mol. Cancer 23, 129 (2024).
pubmed: 38902727 pmcid: 11188176 doi: 10.1186/s12943-024-02040-9
Williams, H. L. et al. The current landscape of spatial biomarkers for prediction of response to immune checkpoint inhibition. npj Precis. Oncol. 8, 178 (2024).
pubmed: 39138341 pmcid: 11322473 doi: 10.1038/s41698-024-00671-1
Evans, S. S., Repasky, E. A. & Fisher, D. T. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat. Rev. Immunol. 15, 335–349 (2015).
pubmed: 25976513 pmcid: 4786079 doi: 10.1038/nri3843
He, M. et al. The crosstalk between DNA-damage responses and innate immunity. Int. Immunopharmacol. 140, 112768 (2024).
pubmed: 39088918 doi: 10.1016/j.intimp.2024.112768
Tong, J. et al. When DNA-damage responses meet innate and adaptive immunity. Cell Mol. Life Sci. 81, 185 (2024).
pubmed: 38630271 pmcid: 11023972 doi: 10.1007/s00018-024-05214-2

Auteurs

Douglas Hanahan (D)

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. douglas.hanahan@epfl.ch.
Agora Cancer Research Center, Lausanne, Switzerland. douglas.hanahan@epfl.ch.
Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland. douglas.hanahan@epfl.ch.
Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland. douglas.hanahan@epfl.ch.

Olivier Michielin (O)

Agora Cancer Research Center, Lausanne, Switzerland.
Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland.
Department of Medicine, University of Geneva (UNIGE), Geneva, Switzerland.

Mikael J Pittet (MJ)

Agora Cancer Research Center, Lausanne, Switzerland.
Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland.
Department of Pathology and Immunology, University of Geneva (UNIGE), Geneva, Switzerland.

Classifications MeSH