PROGNOSTIC ROLE OF TUMOR-INFILTRATING LYMPHOCYTES IN TUMOR MICROENVIRONMENT OF GASTRIC CANCER
Marina A. Pereira1,2, Marcus F. Ramos1,2, Leonardo Cardili1,2, Rafael D. de Moraes1,2, André R. Dias1,2, Venâncio A. Alves1,2, Bruno Zilberstein*1,2, Evandro S. de Mello1,2, Ulysses Ribeiro1,2
1Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil; 2Universidade de Sao Paulo Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, São Paulo, Brazil
INTRODUCTION
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 cancer types. However, due to 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 at our Institute between 2009 and 2019 were retrospectively investigated to perform tissue microarrays. Expression of CD3+ TILs was conducted by immunohistochemical (IHC) and determined by the percentage of positive-stained cells. TIL evaluation was conducted according to TILs intensity (4-point), and the percentage of CD3+ T cells infiltration was classified into a 4-point score based on quartiles. The final score was determined by the sum of the two scores (0-8 points). A score≥4+ was defined as a high-CD3+ expression. Microsatellite instability (MSI), CD4+/CD8+ T cells ratio, and PD-L1 were also evaluated by IHC.
RESULTS
A total of 345 patients with GC were enrolled. The median percentage of staining cells for TILs CD3+ was 48.3% (42.5 – 55). Accordingly, 124 (35.9%) GCs were classified as low-CD3+ and 221 (64.1%) as a high-CD3+ group. Clinical and surgical characteristics were similar between both groups. Poorly differentiated histology (p=0.014), Epstein-Barr virus (EBV) positivity (p<0.001), PD-L1 positive (p=0.001), and CD4<CD8 (p<0.001) were associated with high-CD3+ GC. There was no difference regarding MSI status, pT, pN, and pTNM stage between low- and high-CD3+ groups. In survival analysis, the high-CD3+ group had better disease-free survival (DFS) and overall survival (OS) rates compared to the low-CD3+ GC (p=0.055 and p=0.041, respectively). In the multivariate analysis, total gastrectomy, lymph node metastasis, advanced pT stage, and low-CD3+ were independent factors related to worse survival for both DFS and OS. MSI and CD4+/CD8+ ratio were not significantly associated with survival.
CONCLUSIONS
1. High CD3+ TILs were significantly associated with improved survival and could serve as prognostic biomarkers in GC. 2. CD3+ T cells infiltration was related to both EBV and PD-L1 positive GC and may also assist in the investigation of targets in immunotherapy.
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