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• W4382806945 abstract "Gastric adenocarcinoma (GAC), the fifth most common cancer worldwide, imposes a considerable global health burden. Despite improvements in multidisciplinary therapies, 5-year survival rates remain unsatisfactory (∼25%). In advanced clinical stages, cytotoxic chemotherapy is still the cornerstone of treatment. Recently, PD-1 inhibitors have also shown clinical efficacy in subpopulations of patients with GAC. In this regard, the use of PD-L1 expression by immunohistochemistry as a predictive factor of benefit to immune checkpoint inhibitors has shown inconclusive results, which may reflect the inherent complexity of the antitumoral immune response for a phenotypically heterogeneous disease. Thus, molecular profiling of GAC from the tumor microenvironment perspective through a multi-omics approach is eagerly awaited in order to allow a more precise application of novel therapies in the near future. With the aim to better understand the tumor-immune interface of GAC we identified an internal cohort of 82 patients with a variety of anatomical (proximal/distal), histological (intestinal/diffuse) and biomarker (HER2+/PDL1+/MMRd) subtypes and with available tumor samples that allowed an integrative molecular analysis, including: a) whole-exome sequencing; b) gene-expression assessed by the nCounter PanCancer IO 360 panel that interrogates 770 genes associated with the immune response; and c) multiplex protein expression at spatial resolution trough the GeoMx Digital Spatial Profiler designed to analyze 36 immuno-oncology targets at different regions (invasive margin and tumor center) and compartments (PanCK+ tumoral cells and CD45+ immune cells). Molecular findings were validated in an external cohort of 295 GACs from the TCGA with available muti-omics data. Unsupervised clustering by immune-related gene-expression identified a subgroup of GAC that includes 52% of the tumors, the so-called Inflamed class, characterized mainly by signatures of tumor immunogenicity (antigen presentation) and anti-tumor immune activity (interferon gamma). Gene-expression deconvolution of immune cells inferred increased amounts of macrophages, B cells and T cells (particularly exhausted CD8+) in the Inflamed class when compared with the rest of the tumors. Targetable co-inhibitory receptors such are PD1, CTLA4, LAG3 and TIGIT were overexpressed in the Inflamed class at RNA level, whereas VEGFA was downregulated. In terms of spatial protein profiling, tumors from the Inflamed class were characterized by increased expression of HLA-DR and CD44 by tumoral cells and STING by immune cells, both specifically in the tumor center and indicating activation of an anti-tumoral immune response. There was an enrichment of PIK3CA, ARID1A and RHOA mutations in the Inflamed class, whereas TP53 mutations and chromosomal instability were less frequently present. From the clinical-pathological perspective, the Inflamed class was associated with occidental patients and diffuse histology. Finally, A 10-gene RNA signature was developed for the identification of GACs belonging to the Inflamed class. Integrative molecular analysis of the tumor microenvironment of GAC identifies an Inflamed class of tumors that complements previously proposed tumor-based molecular clusters (CIN, MSI, EBV, GS). Such findings may provide the rationale for exploring novel immunotherapeutic approaches for biomarker-enriched populations in order to improve GAC patient’s survival by means of a paradigm shift in precision immune-oncology." @default.
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• W4382806945 date "2023-06-01" @default.
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• W4382806945 title "PD-2 Comprehensive immunophenotyping of gastric adenocarcinoma identifies an inflamed class of tumors amenable to immunotherapies" @default.
• W4382806945 doi "https://doi.org/10.1016/j.annonc.2023.04.029" @default.
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