Immune profiling of gastric adenocarcinomas in EU and LATAM countries identifies global differences in immune subgroups and microbiome influence

Abstract

Immune profiling; Gastric adenocarcinomas; Microbiome

Perfil inmunológico; Adenocarcinomas gástricos; Microbioma

Perfil immunològic; Adenocarcinomes gàstrics; Microbioma

Background Gastric cancer (GC) patients from European (EU) and especially Latin American (LATAM) countries are underrepresented in previous large-scale multi-omic studies that have identified clinically relevant subgroups. The LEGACY study aimed to profile the molecular and immunological features of GCs from EU and LATAM countries. Methods Tumor biopsies from 95 EU and 56 LATAM GCs were profiled with immunohistochemistry (CD3, CD8, FOXP3, PD-L1, MSI and HER2), Nanostring mRNA expression analyses, and microbiome sequencing. Results Immune profiling identified four distinct immune clusters: a T cell dominant cluster with enriched activation pathways, a macrophage dominant cluster and an immune excluded microenvironment which were equally distributed among the countries. A fourth cluster of mostly Mexican patients consisted of excessive T cell numbers accompanied by enhanced cytokine signaling in absence of enhanced antigen presentation and cytotoxicity signatures and a strong association with H. pylori infection. Discussion Both EU and LATAM countries have GCs with a T cell inflamed microenvironment that might benefit from checkpoint inhibition. We identified a highly inflamed GC subgroup that lacked antigen presentation and cytotoxicity associated with H. pylori CagA-positive strains, suggesting their contribution to tumor immune tolerance. Future studies are needed to unravel whether these cancers benefit from immunotherapy as well.

This study was funded by the European Union’s Horizon 2020 research and innovation program (Grant agreement No GA825832). The European Union was not involved in the collection, analysis and interpretation of data, in writing future manuscripts or deciding to submit manuscripts for publication. SD is supported by the Dutch Cancer Society, the Netherlands Organization for Scientific Research (NWO) and Oncode Institute. This work was supported in Chile by ANID-FONDAP-152220002 & 15130011 (1523A0008), PROGRAMA ICM-ANID, ICN2021_045, ANID FONDECYT 1220586. The funding for Mexico was supported by CONAHCyT N°297681 (CELAC and European Consortium for Personalized Medicine Approach to Gastric Cancer (LEGACy).