Prognostic implications of tumor-infiltrating lymphocytes within the tumor microenvironment in gastric cancer. 2024

Marina Alessandra Pereira, and Marcus Fernando Kodama Pertille Ramos, and Leonardo Cardili, and Rafael Dyer Rodrigues de Moraes, and André Roncon Dias, and Daniel Jose Szor, and Bruno Zilberstein, and Venancio Avancini Ferreira Alves, and Evandro Sobroza de Mello, and Ulysses Ribeiro
Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil. Electronic address: marina.pereira@hc.fm.usp.br.

BACKGROUND Tumor-infiltrating lymphocytes (TILs) play a regulatory role in the tumor-associated immune response and are important in the prognosis and treatment response of several cancers. However, because of its heterogeneity, the prognostic value of TILs in gastric cancer (GC) is still controversial. Thus, this study aimed to investigate the association between the density of TILs and patients' outcomes in GC. METHODS Patients with gastric adenocarcinoma who underwent curative intent gastrectomy were retrospectively investigated. The groups for analysis were determined on the basis of TIL intensity and percentage of CD3+ T-cell infiltration by immunohistochemical. Furthermore, Epstein-Barr virus (EBV), microsatellite instability (MSI), T-cell ratio of CD4 to CD8, and programmed death protein ligand 1 (PD-L1) status were evaluated. RESULTS A total of 345 patients were enrolled: 124 patients with GCs (35.9%) were classified as the low-CD3+ TIL group, and 221 patients with GCs (64.1%) were classified as the high-CD3+ TIL group. Poorly differentiated histology (P = .014), EBV-positive status (P < .001), PD-L1-positive status (P = .001), and CD4 < CD8 (P < .001) were associated with high-CD3+ GC. There was no difference regarding MSI status, the degree of tumor invasion (pT), the presence of lymph node metastasis, and pTNM stage between low- and high-CD3+ groups. In survival analysis, the high-CD3+ group had better disease-free survival and overall survival rates than had the low-CD3+ group (P = .055 and P = .041, respectively). In the multivariate analysis, total gastrectomy, lymph node metastasis, advanced pT stage, and low CD3+ levels were independent factors related to worse survival. CONCLUSIONS High CD3+ TILs levels were significantly associated with improved survival and could serve as prognostic biomarkers in GC. In addition, CD3+ T-cell infiltration was related to both EBV-positive and PD-L1-positive GC and may assist in the investigation of targets in immunotherapy.

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