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. 2025 May;132(9):783-792.
doi: 10.1038/s41416-025-02979-6. Epub 2025 Mar 20.

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

Tessa S Groen-van Schooten #  1   2   3 , Manuel Cabeza-Segura #  4 , Rui M Ferreira  5   6 , Carolina Martínez-Ciarpaglini  7 , Rita Barros  5   6   8   9 , João Santos-Antunes  10 , Andreia Costa  11 , Edith A Fernández-Figueroa  12 , Leonardo Lino-Silva  13 , Angélica Ixtaccihuatl Hernandez-Guerrero  14 , Erika Ruiz-García  15   16 , Carmelo Caballero  17 , Hugo Boggino  17 , Cinthia Gauna  18 , Daniel Cantero  19 , Berenice Freile  20 , Federico Esteso  20 , Juan O Connor  20 , Arnoldo Riquelme  21 , Gareth Owen  22 , Erick Riquelme  23 , Juan Carlos Roa  24 , Gonzalo Latorre  25 , Marcelo Garrido  26 , Fiorella Ruiz-Pace  27 , Marc Diez García  28 , Maria Alsina  28   29 , Florian Lordick  30 , Judith Farrés  31 , Juan Antonio Carbonell-Asins  32 , Rossana Villagrasa  33 , Rita Pereira  19 , Roos E Pouw  34 , Elena Jimenez-Martí  4 , Ana Miralles  4 , Rodrigo Dientsmann  27 , Ceu Figueiredo  5   6   9 , Fatima Carneiro  5   6   8   9 , Andrés Cervantes  4   35 , Sarah Derks  36   37   38 , Tania Fleitas  39
Affiliations

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

Tessa S Groen-van Schooten et al. Br J Cancer. 2025 May.

Abstract

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.

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Conflict of interest statement

Competing interests: MA discloses consultancy, advisory roles, honoraria from Amgen, AstraZeneca, Beigene, Drangofly Therapeutics, Jazz Pharmaceuticals, BMS, Lilly, Novartis and MSD. Institutional research funding from Merck. FL reports institutional grants from: Astra Zeneca, Beigene, BMS, Daiichi Sankyo and Gilead, and personal fees from: Amgen, ArtTempi. Astellas, Astra Zeneca, Bayer, Biontech, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Elsevier, Incyte, Medscape, MedUpdate, Merck Serono, MSD, PAGE, Roche, Servier, StreamedUp!, VJ Oncology, all outside the submitted work. TF discloses advisory roles honoraria from Amgen, AstraZeneca, Beigene, BMS and MSD. Institutional research funding from Gilead. Speaker honoraria from Amgen, Servier, BMS, MSD, Lilly, Roche, Bayer. JF was full-time employee at Anaxomics Biotech at the time of the study. RD declares advisory role for Roche, Foundation Medicine, AstraZeneca received a speaker’s fee from Roche, Ipsen, Amgen, Servier, Sanofi, Libbs, Merck Sharp & Dohme, Lilly, AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, GlaxoSmithKline, Gilead, research grants from Merck, Novartis, Daiichi-Sankyo, GlaxoSmithKline and AstraZeneca, and is investor in Trialing Health, S.L. AC declares institutional grants from Actuate Therapeutic Adaptimmune, Affimed, Amgen, Astellas Pharma, Astra Zeneca, Bayer, F. STAR Therapeutics, Genentech, Gilead, Janssen, Lilly, MedImmune, Merck Serono, MSD, Natera, Novartis, Ribon Therapeutics, Roche, Takeda. Speaker honoraria from Amgen, Foundation Medicine, Merck Serono, Roche. Advisory role for Abbvie, AnHeart Therapeutics, GSK, Merck Serono, Roche, Transgene, Amgen. Leadership role as ESMO president, ESMO OPEN Associate Editor, Annals of Oncology Associate Editor, and Cancer & treatment reviews, editor in chief. RMF and CF declares their own patent WO/2018/169423 on microbiome markers for gastric cancer. SD reports: a consultant or advisory role for BMS (related to checkpoint inhibitors); research funding, medication supply, or both from Incyte (related to checkpoint inhibitors); and speaker roles for Servier, BMS, and Benecke. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics approval and consent to participate: The study has been conducted according to the principles of the Declaration of Helsinki (Fortaleza, Brazil, October 2013), following the Medical Research Involving Human Subjects Act and Good Clinical Practice standards. The study can be found under ClinicalTrials.gov Identifier: NCT04015466, and NCT03957031, July 11, 2019. The study protocol has been approved by the ethics committee of all patient-recruiting centres: the ethics committee of University Clinical Hospital of Valencia, Spain (reference number 2018/205), the institutional review board of VU University Medical Center Amsterdam (reference number 2019.355. NL 69480.02919), the ethics committee of Instituto de Previsión Social, Asuncion-Paraguay (reference number CA N°11-020/19), the ethical research committee of Instituto Alexander Fleming, Buenos Aires Argentina (Resolution July 25th, 2019, for LEGACy study 1 and 2 and October 3rd, 2019 for LEGACy study 3); the ethical committee of Instituto Nacional de Cancerología (INCAN, México (reference number INCAN/CEI/0486/19). The ethics committee of the University Center of Sao Joao and Medicine Faculty of Porto University, Portugal (reference 100/019), the scientific ethical Committee Pontificia University of Chili, reference 180806007, and the Drug research ethics committee of Valld’Hebron University Hospital, Barcelona, Spain with references PR (AG)387/2019 approved on October 29th, 2019 for LEGACy study 1, PR (AG)388/2019 approved in December 13th 2019 for LEGACy study 2 and PR (AG)419/2019 approved in January 30th, respectively. All participants provided written informed consent before study enrolment. Each data-contributing partner has undergone online ethical and data training before the beginning of data collection and has managed access to the data of their centre through this security system. Inside this system, a patient ID generator has generated a unique code for each participating patient to maintain data privacy.

Figures

Fig. 1
Fig. 1. Study outline.
EU Europe, LATAM Latin America.
Fig. 2
Fig. 2. Transcriptomic analysis identified distinct GC immune clusters.
A Unsupervised hierarchical clustering heatmap based on transcriptional cell type scores identifying two main GC immune clusters: cluster 1 (subdivided into clusters 1A, 1B and 1C) and cluster 2. B IHC data validating the four immune scenarios detected by the transcriptomic analysis. Adj p < 0.05 were considered as statistically significant. C Differential pathways expression across the four distinct immune clusters. P < 0.05 were considered as statistically significant. D Heatmap showing the z-score mRNA expression of gene targets for ICIs and new immunotherapies: PDCD1, CD274, CTLA4, TNFRSF4, LAG3, IDO1, and HAVCR2. EU Europe, LATAM Latin America.
Fig. 3
Fig. 3. Gastric cancer immune profiles show geographic specificities.
A Distribution of the four immune cluster showed differences between EU and LATAM continents (p = 0.001). B Distribution of the four immune clusters showed differences across countries (p = 0.001). C Immune cell type abundance comparison between EU and LATAM GCs patients with and without Mexico. EU Europe, LATAM Latin America, w/o Mex without Mexican population.
Fig. 4
Fig. 4. Relationship between the microbiota and the immune profiling of gastric cancer patients.
A Heatmap showing a supervised clustering analysis of GCs based on the top 15 most abundant genera. B Abundance of Helicobacter sp. and Lactobacillus sp. between immune clusters in all cases, per EU and LATAM GCs, and in LATAM excluding Mexican GCs.
See this image and copyright information in PMC

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