Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment.

Humans Stomach Neoplasms / genetics Endothelial Cells Tumor Microenvironment Gene Expression Profiling Transcriptome Single-Cell Analysis
Gastric cancer Single-cell RNA transcriptomics Tumor microenvironment

Journal

Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660

Informations de publication

Date de publication:
22 12 2022
Historique:
received: 08 12 2021
accepted: 01 12 2022
entrez: 22 12 2022
pubmed: 23 12 2022
medline: 27 12 2022
Statut: epublish

Résumé

The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized. We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival. Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.

Sections du résumé

BACKGROUND
The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized.
RESULTS
We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival.
CONCLUSIONS
Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.

Identifiants

DOI: 10.1186/s13059-022-02828-2 PMID: 36550535 PMC: PMC9773611
pubmed: 36550535
doi: 10.1186/s13059-022-02828-2
pii: 10.1186/s13059-022-02828-2
pmc: PMC9773611
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

265

Informations de copyright

© 2022. The Author(s).

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Auteurs

Boxi Kang (B)

BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China.

Jordi Camps (J)

Biomedical Data Science, Research & Early Development Oncology, Bayer AG, Berlin, Germany.

Biao Fan (B)

Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Hongpeng Jiang (H)

Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.

Mahmoud M Ibrahim (MM)

Biomedical Data Science, Research & Early Development preMed, Bayer AG, Wuppertal, Germany.

Xueda Hu (X)

BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China.

Shishang Qin (S)

BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China.

Dennis Kirchhoff (D)

Immuno Oncology, Research & Early Development Oncology, Bayer AG, Berlin, Germany.

Derek Y Chiang (DY)

Biomedical Data Science, Research & Early Development Oncology, Bayer US, Cambridge, MA, USA.

Shan Wang (S)

Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.
Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, China.
Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Beijing, China.

Yingjiang Ye (Y)

Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.
Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, China.
Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Beijing, China.

Zhanlong Shen (Z)

Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China. shenzhanlong@pkuph.edu.cn.
Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, China. shenzhanlong@pkuph.edu.cn.
Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Beijing, China. shenzhanlong@pkuph.edu.cn.

Zhaode Bu (Z)

Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. buzhaode@cjcrcn.org.

Zemin Zhang (Z)

BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China. zemin@pku.edu.cn.
Peking-Tsinghua Centre for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. zemin@pku.edu.cn.

Helge G Roider (HG)

Oncology Precision Medicine, Research & Early Development Oncology, Bayer AG, Berlin, Germany. helge.roider@bayer.com.

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