Immunogenomic characterization in gastric cancer identifies microenvironmental and immunotherapeutically relevant gene signatures
Author(s) -
Han Xiao,
Lu Heyue,
Tang Xiaojun,
Zhao Yao,
Liu Hongxue
Publication year - 2022
Publication title -
immunity, inflammation and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 18
ISSN - 2050-4527
DOI - 10.1002/iid3.539
Subject(s) - immune system , tumor microenvironment , biology , microsatellite instability , immunotherapy , cancer research , stromal cell , invadopodia , immunology , cancer immunotherapy , immune checkpoint , cancer , phenotype , cancer cell , gene , genetics , allele , microsatellite
Abstract 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.