RESUMO
INTRODUCTION: Gastric epithelial tumors exhibit morphological heterogeneity, diverse biological behaviors, and different oncopathological pathways. The Cancer Genome Atlas (TCGA) proposed a molecular classification of gastric adenocarcinomas based on genetic and molecular findings, which shows particular characteristics of diagnosis, prognosis, and indirectly, therapeutic alternatives. Within this classification, Epstein-Barr virus-positive (EBV+) and high microsatellite instability (MSI-H) subtypes stand out as subtypes that present a less aggressive biological behavior and a highly mutilated phenotype. This study conducted a systematic review with an emphasis on epidemiological and prognostic factors based on the molecular classification proposed by TCGA. METHODS: A broad, comprehensive, and reproducible search with methodological rigor was conducted for study selection using the ROBINS-I and GRADEpro protocols and appropriate combinations of keywords. RESULTS: A total of 25 studies were selected: six with a complete classification similar to TCGA and 19 with a distinction between MSI-H and EBV+. The application of meta-analysis calculations reinforces the prevalence of positive Epstein-Barr adenocarcinomas in males and high microsatellite instability in females, with a high level of certainty of evidence and low risk of bias in the analyzed studies due to the rigorous methods used. CONCLUSION: The molecular classification proposed by TCGA shows limited dissemination, with MSI-H and EBV+ subtypes being the most researched, probably due to the benefit of the association with immunotherapies. However, the subclassification cannot be restricted to less than a quarter of the cases, and improvements in this aspect are urgent for the construction of knowledge on this important topic of global health.
Assuntos
Adenocarcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Masculino , Feminino , Humanos , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/complicações , Instabilidade de Microssatélites , Repetições de Microssatélites , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/patologiaRESUMO
OBJECTIVE: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity. DESIGN: We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. RESULTS: We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-ß may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13 + tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. CONCLUSION: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.