Background: Multiple molecular subtypes with distinct clinical outcomes in gastric cancer have been identified. Nonetheless, the immunogenomic subtypes of gastric cancer and its mediated tumor microenvironment (TME) characterizations have not been fully understood.
Methods: Six gastric cancer cohorts with 1506 samples were obtained. Unsupervised methods were used to perform immunogenomic phenotype clustering. The least absolute shrinkage and selection operator regression method was used to construct immunogenomic characterization score (IGCS).
Results: Three distinct immunogenomic phenotypes were determined. We observed a prominent survival difference between three phenotypes. The TME cell-infiltrating characteristics under these three phenotypes were highly consistent with three immune subtypes of tumors. Cluster 1, was characterized by the "immune-desert" phenotype, with relatively lower cell infiltration level (type 1 "cold tumor"); Cluster 2, characterized by "immune-inflamed" phenotype, with abundant innate and adaptive immune cell infiltration ("hot tumor"); Cluster 3, characterized by "immune-excluded" phenotype, with significant stromal activation and inactivated immune cell infiltration (type 2 "cold tumor"). We demonstrated IGCS signature was significantly correlated with TME inflammation and stroma activity, molecular subtypes, genetic variation, microsatellite instability, immune checkpoint molecules, and patient prognosis. High IGCS subtype, with poorer survival and enhanced stromal activity, presented an immune-exclusion and non-inflamed TME characterization. Low IGCS, related to increased mutation/neoantigen load and microsatellite instability, showed enhanced responses to anti-checkpoint immunotherapy. Four immunotherapy cohorts confirmed patients with low IGCS exhibited prominently enhanced clinical responses and treatment advantages.
Conclusions: This study demonstrated the immunogenomic characterizations could play a crucial role in shaping the complexity and diversity of tumor microenvironment. Targeting tumor immunogenomic characteristic in order for changing adverse phenotypes may contribute to exploiting the novel immunotherapy combination strategies or novel immunotherapeutic drugs, and promoting the advance of tumor personalized immunotherapy.
Keywords: immune checkpoint; immunogenomic phenotype; immunotherapy; prognosis; tumor microenvironment.
© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.