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

## TL;DR

This study compares immune profiles of gastric cancer in European and Latin American patients, revealing distinct immune subgroups and the influence of the microbiome and H. pylori infection.

## Contribution

The study identifies a novel immune subgroup in Mexican patients with unique T cell and cytokine features linked to H. pylori CagA-positive strains.

## Key findings

- Four immune clusters were identified, with one cluster predominantly from Mexico showing high T cell counts and cytokine signaling.
- A T cell inflamed microenvironment was found in both EU and LATAM GCs, suggesting potential benefit from checkpoint inhibition.
- A subgroup with high inflammation but low antigen presentation and cytotoxicity was associated with H. pylori CagA-positive strains.

## Abstract

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.

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.

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.

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.