4.7 Article

Identification and validation of tumour microenvironment-based immune molecular subgroups for gastric cancer: immunotherapeutic implications

Journal

CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 69, Issue 6, Pages 1057-1069

Publisher

SPRINGER
DOI: 10.1007/s00262-020-02525-8

Keywords

Gastric cancer; Tumour-immune microenvironment; Immune molecular subgroups; Virtual microdissection; Immune checkpoint blockade

Funding

  1. Incubating Program for Clinical Research and Innovation of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University [PYMDT-001]
  2. Science and Technology Commission of Shanghai Municipality [16441906903]
  3. Three-year action plan for Shin Kang of Shanghai [16CR4005A]
  4. Fundamental Research Funds for the Central Universities grants of China [2632018FY04]
  5. Double First-Class University Project [CPU2018GY09]

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Background Immunotherapy could trigger durable response in advanced gastric cancer, but it only benefits a minority of patients. We aimed to propose a robust molecular classification of gastric cancer microenvironment to identify ideal candidates for tailoring effective immunotherapy. Methods A training cohort of 375 gastric cancer samples with RNA sequencing data was analysed. We virtually microdissected tumour, stromal, and immune cell gene expression patterns employing a non-negative matrix factorization algorithm. These expression patterns were annotated using immune- and stromal-related gene signatures. Validation of immunogenomic classification was performed across six microarray datasets of 1406 samples. Results We found approximately half of gastric cancer samples to have higher immune cell infiltrates, PD-L1 expression, markers of cytolytic activity, and fewer copy number aberrations (all P < 0.05). We termed this group of tumours the Immune Class, which incorporated two components, namely Immune Activation and Immunosuppressive Subtype, according to immunosuppressive or activated microenvironment. Immune Activation Subtype was associated with improved survival in multivariate survival analysis and shared similar genomic characteristics with responders of anti-PD-1 therapy. Immunosuppressive Subtype featured high immune infiltration, stromal enrichment, and transforming growth factor (TGF)-beta signalling pathway activation and correlated with non-responsiveness signature of checkpoint blockade therapy, which might be suitable for anti-PD-L1 and anti-TGF-beta combined therapy. Conclusions We proposed and independently validated three reproducible immune molecular subtypes of gastric cancer, which may provide implications for patient selection of immunotherapy.

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