Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control.
Antigen
Breast cancer
Immunology
Oncology
Radiation therapy
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
07
04
2020
accepted:
13
01
2021
pubmed:
22
1
2021
medline:
21
9
2021
entrez:
21
1
2021
Statut:
ppublish
Résumé
Neoantigens generated by somatic nonsynonymous mutations are key targets of tumor-specific T cells, but only a small number of mutations predicted to be immunogenic are presented by MHC molecules on cancer cells. Vaccination studies in mice and patients have shown that the majority of neoepitopes that elicit T cell responses fail to induce significant antitumor activity, for incompletely understood reasons. We report that radiotherapy upregulates the expression of genes containing immunogenic mutations in a poorly immunogenic mouse model of triple-negative breast cancer. Vaccination with neoepitopes encoded by these genes elicited CD8+ and CD4+ T cells that, whereas ineffective in preventing tumor growth, improved the therapeutic efficacy of radiotherapy. Mechanistically, neoantigen-specific CD8+ T cells preferentially killed irradiated tumor cells. Neoantigen-specific CD4+ T cells were required for the therapeutic efficacy of vaccination and acted by producing Th1 cytokines, killing irradiated tumor cells, and promoting epitope spread. Such a cytotoxic activity relied on the ability of radiation to upregulate class II MHC molecules as well as the death receptors FAS/CD95 and DR5 on the surface of tumor cells. These results provide proof-of-principle evidence that radiotherapy works in concert with neoantigen vaccination to improve tumor control.
Identifiants
pubmed: 33476307
pii: 138740
doi: 10.1172/JCI138740
pmc: PMC7919731
doi:
pii:
Substances chimiques
Antigens, Neoplasm
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA198533
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201246
Pays : United States
Références
Nature. 2019 Jan;565(7738):234-239
pubmed: 30568305
Cancer Res. 2017 Jan 15;77(2):312-319
pubmed: 27872096
Mol Cell Proteomics. 2015 Mar;14(3):658-73
pubmed: 25576301
Nature. 2015 Apr 30;520(7549):692-6
pubmed: 25901682
Cancer Res. 1992 Mar 15;52(6):1399-405
pubmed: 1540948
J Immunol. 1996 May 1;156(9):3308-14
pubmed: 8617954
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Nat Rev Cancer. 2020 Apr;20(4):203-217
pubmed: 32161398
JAMA Oncol. 2019 Jul 11;:
pubmed: 31294749
Cancer Immunol Res. 2020 Apr;8(4):465-478
pubmed: 32047024
Nat Rev Immunol. 2018 Mar;18(3):168-182
pubmed: 29226910
N Engl J Med. 2014 Dec 4;371(23):2189-2199
pubmed: 25409260
J Exp Med. 2007 Jan 22;204(1):49-55
pubmed: 17210731
Cell. 1990 Aug 10;62(3):563-7
pubmed: 2199065
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Cancer Res. 2018 Aug 15;78(16):4573-4585
pubmed: 29752262
Nature. 1991 Dec 19-26;354(6354):528-31
pubmed: 1758495
Oncoimmunology. 2020 Jun 22;9(1):1771925
pubmed: 32923128
Nature. 2017 Jul 13;547(7662):217-221
pubmed: 28678778
Cancer Immunol Immunother. 2000 Apr;49(1):34-45
pubmed: 10782864
Genome Biol. 2014;15(12):550
pubmed: 25516281
Immunity. 2000 Oct;13(4):529-38
pubmed: 11070171
Cell. 1989 Jul 28;58(2):305-15
pubmed: 2473842
J Immunol. 1993 Jul 1;151(1):1-10
pubmed: 8392095
Cancer Res. 2000 May 15;60(10):2710-5
pubmed: 10825145
Respir Res. 2019 Jan 17;20(1):11
pubmed: 30654796
Nature. 2017 Jul 13;547(7662):222-226
pubmed: 28678784
Front Immunol. 2020 Jan 24;11:27
pubmed: 32117226
Nat Med. 2018 Dec;24(12):1845-1851
pubmed: 30397353
Nature. 2017 Aug 24;548(7668):466-470
pubmed: 28759889
Nat Rev Immunol. 2003 Dec;3(12):952-61
pubmed: 14647477
Bioinformatics. 2016 Feb 15;32(4):511-7
pubmed: 26515819
Front Immunol. 2019 Jun 24;10:1392
pubmed: 31293573
J Immunol. 2000 Dec 1;165(11):6123-32
pubmed: 11086045
J Virol. 1998 Nov;72(11):9404-6
pubmed: 9765498
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
J Immunol. 2018 Mar 15;200(6):2004-2012
pubmed: 29436413
Science. 2014 May 9;344(6184):641-5
pubmed: 24812403
Genome Med. 2019 Jun 20;11(1):40
pubmed: 31221199
Clin Cancer Res. 2009 Sep 1;15(17):5379-88
pubmed: 19706802
Cell Rep. 2018 Apr 03;23(1):239-254.e6
pubmed: 29617664
Cancer Immunol Res. 2020 Mar;8(3):409-420
pubmed: 31907209
Nature. 2019 Jan;565(7738):240-245
pubmed: 30568303
Nature. 2005 Aug 25;436(7054):1186-90
pubmed: 15995699
Science. 2018 Oct 12;362(6411):
pubmed: 30309915
N Engl J Med. 2017 Dec 21;377(25):2500-2501
pubmed: 29262275
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Cancer Res. 2012 Mar 1;72(5):1081-91
pubmed: 22237626
Nature. 2019 Oct;574(7780):696-701
pubmed: 31645760
J Exp Med. 2014 Oct 20;211(11):2231-48
pubmed: 25245761
J Exp Med. 2010 Mar 15;207(3):637-50
pubmed: 20156971
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E484-91
pubmed: 24434553
Science. 2015 Apr 3;348(6230):69-74
pubmed: 25838375
Nat Med. 2015 Jan;21(1):81-5
pubmed: 25531942
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9730-5
pubmed: 8790399
Cell. 2020 Jun 25;181(7):1612-1625.e13
pubmed: 32497499
Genome Res. 2012 Mar;22(3):568-76
pubmed: 22300766
Cell. 2018 Oct 4;175(2):416-428.e13
pubmed: 30245014
Nat Methods. 2013 Jan;10(1):19-22
pubmed: 23547293
Science. 2017 Jul 28;357(6349):409-413
pubmed: 28596308
J Exp Med. 2006 May 15;203(5):1259-71
pubmed: 16636135