226P - Profiling of gastric adenocarcinomas from EU and LATAM countries identifies distinct tumor immune subgroups and a central role of the tumor microbiome in shaping the immune microenvironment

Background

Gastric cancer (GC) is in the top list of most deadly cancers worldwide. Previous large-scale multi-omics studies have identified clinically relevant subgroups of patients. However, patients from European (EU) and especially Latin American (LATAM) countries are underrepresented in these studies. The present study, which is part of the European LEGACy project, aimed to profile the molecular and immunological features of GCs from EU and LATAM countries and explore leads for alternative treatment strategy.

Methods

Formalin-fixed and paraffin-embedded tumor biopsies from 95 EU and 56 LATAM treatment-naive, advanced gastric and gastroesophageal junction adenocarcinomas were collected for immune phenotyping with immunohistochemistry (CD3, CD8, FOXP3, PD-L1) and Nanostring mRNA expression analyses (IO panel). Additional fresh frozen biopsies from adjacent non-tumor gastric mucosa were sequenced for microbiota analyses.

Results

Immune profiling identified four distinct immune clusters. One cluster consisted of an excessive number of T cells accompanied by enhanced angiogenesis and cytokine signaling in absence of enhanced antigen presentation and cytotoxicity signatures. Microbiota analyses identified a strong association with Helicobacter pylori infection. Almost all GCs belonging to this cluster were from Mexico. The three other clusters consistent of T cell dominant, a macrophage dominant and an immune excluded microenvironment which were more equally distributed among the countries. The T cell dominant cluster was enriched for antigen presentation and cytotoxicity indicating an activated antitumor immune response.

Conclusions

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 in Mexico that lacked antigen presentation and cytotoxicity indicating an anti-H. pylori instead of an anti-tumor immune response. Future studies are needed to unravel whether these cancers benefit from immunotherapy as well.

Clinical trial identification

NCT04015466.

Legal entity responsible for the study

INCLIVA Biomedical Research Institute.

Funding

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. 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).

Disclosure

E. Ruiz: Financial Interests, Personal, Advisory Board: Roche, Amgen, BMS, Bayer, Pfizer, Takeda; Financial Interests, Personal, Invited Speaker: Roche, Merck, Astellas; Non-Financial Interests, Personal, Leadership Role: ASCO. J.M.R. O'Connor: Financial Interests, Personal, Invited Speaker: Merck Serono, BMS, Bayer, Servier, Pfizer; Financial Interests, Personal, Advisory Board: MSD. M. Alsina Maqueda: Financial Interests, Personal, Other, advisory board and invited speaker: MSD, Beigene, Novartis; Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Amgen, Drangofly Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Lilly; Non-Financial Interests, Personal, Principal Investigator, Investigator Initiated Trial: Merck Serono; Non-Financial Interests, Personal, Leadership Role, Co-leadership of the Gastric Cancer Task Force: EORTC GICTG. F. Lordick: Financial Interests, Personal, Advisory Board: Astellas, BMS, Beigene, BioNTech, MSD, Daiichi Sankyo, PAGE; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Eli Lilly, Imedex, Incyte, MSD, Med Update, Medscape, Merck Serono, Servier, Streamed Up!, Daiichi Sankyo, Art Tempi, Astellas; Financial Interests, Personal, Writing Engagement: Deutscher Ärzteverlag, Elsevier, Iomedico; Financial Interests, Institutional, Research Grant: BMS, Gilead, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, Beigene. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, GSK, Takeda, Janssen, Gilead, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche, Foundation Medicine; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinico-genomics cohorts; Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis, AstraZeneca, Daiichi Sankyo, GSK. A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck Serono, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Personal, Other, Scientific Director: INCLIVA Biomedical Research Institute. S. Derks: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Invited Speaker: BMS, Servier; Financial Interests, Institutional, Funding, sponsoring investigator initiated study: Incyte. T.C. Fleitas: Financial Interests, Personal, Invited Speaker, Update on the ongoing treatment strategies for GEA: Servier; Financial Interests, Personal, Invited Speaker, The clinical impact of NRTK strategies in GI tumors: Bayer; Financial Interests, Personal, Invited Speaker, Invited as a speaker in an educational session; Bristol, Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in an educational session: Bristol, MSD, Lilly, Roche; Financial Interests, Personal, Advisory Board, update on the state of the art: AstraZeneca; Financial Interests, Personal, Advisory Board, Update on the state of the art: MSD; Financial Interests, Personal, Advisory Board, update on the state of the art of gastric cancer tumors: Amgen; Non-Financial Interests, Personal, Principal Investigator, PI of SURPASS-2 study: Adapt Immune; Non-Financial Interests, Personal, Principal Investigator, PI of a clinical trial in GEA tumors: Daiichi Sanyo; Non-Financial Interests, Personal, Principal Investigator, PI of a clinical trial: Beigene; Non-Financial Interests, Personal, Principal Investigator, Matterhorn clinical trial: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Fortitude 102: Amgen. All other authors have declared no conflicts of interest.