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BACKGROUND: Gastroesophageal adenocarcinomas (GEA) are heterogeneous cancers where immune checkpoint inhibitors (ICI) have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr Virus (EBV) positive subtypes. ICI responses are markedly lower in diffuse/genome-stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies.; PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (TCGA) (N=453 GEAs) and archival GEA resection specimen (N=63). TCGA RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristic within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses.; RESULTS: Our results confirmed substantial heterogeneity in TME between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+T cells, macrophages and B cells and, in 50% of cases, evidence for tertiary lymphoid structures (TLSs). In contrast, CIN cancers possessed CD8+T cells predominantly at the invasive margin while tumor associated macrophages (TAMs) showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1.; CONCLUSION: These results reveal the diversity of immune phenotypes of GEA. Half of GS GCs have TLSs and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities. Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

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Background Gastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied. The LEGACy study is a Horizon 2020 funded multi-institutional research approach to 1) detail the epidemiological features including risk factors of GC in current time and 2) develop cost-effective methods to identify and integrate biological biomarkers needed to guide diagnostic and therapeutic approaches with the aim of filling the knowledge gap on GC in these areas. Methods This observational study has three parts that are conducted in parallel during 2019–2023 across recruiting centers from four EU and four LATAM countries: Part 1) A case-control study (800 cases and 800 controls) using questionnaires on candidate risk factors for GC, which will be correlated with clinical, demographic and epidemiological parameters. Part 2) A case-control tissue sampling study (400 cases and 400 controls) using proteome, genome, microbiome and immune analyses to characterize advanced (stage III and IV) GC. Patients in this part of the study will be followed over time to observe clinical outcomes. The first half of samples will be used as training cohort to identify the most relevant risk factors and biomarkers, which will be selected to propose cost-effective diagnostic and predictive methods that will be validated with the second half of samples. Part 3) An educational study, as part of our prevention strategy (subjects recruited from the general public) to test and disseminate knowledge on GC risk factors and symptoms by a questionnaire and informative video. Patients could be recruited for more than one of the three LEGACy studies. Discussion The LEGACy study aims to generate novel, in-depth knowledge on the tumor biological characteristics through integrating epidemiological, multi-omics and clinical data from GC patients at an EU-LATAM partnership. During the study, cost-effective panels with potential use in clinical decision making will be developed and validated. Trial registration ClinicalTrials.gov Identifiers: Part 1: NCT03957031. Part 2: NCT04015466. Part 3: NCT04019808.