Lymphocyte-Activation Gene 3 Expression Associates With Poor Prognosis And Immunoevasive Contexture In Epstein-Barr Virus-Positive And Mlh1-Defective Gastric Cancer Patients

Lymphocyte activation gene 3 (LAG-3) is a transmembrane immune checkpoint that facilitates immune escape via suppressing T-cell-mediated anti-tumor immunity. The role of LAG-3 in gastric cancer is little known. Consequently, we assessed the clinical significance of LAG-3 in gastric cancer. In our study, patients with gastric cancer from Zhongshan Hospital (n = 464) and data from the Asian Cancer Research Group (n = 300) were analyzed. LAG-3(+) cell infiltration and other immune contexture in gastric cancer were detected by immunohistochemistry. Kaplan-Meier curves and log-rank test were used for survival analyses. Intratumoral LAG-3(+) cells mainly accumulated in Epstein-Barr virus (EBV)-positive (EBV subtype) and MLH1-defective (dMLH1 subtype) gastric cancer. Furthermore, LAG-3(+) cell infiltration was strongly associated with inferior clinical outcomes in patients with these two subtypes of gastric cancer. Moreover, we found intratumoral LAG-3(+) cell high infiltration was associated with an immunoevasive contexture featured by decreased IFN-gamma(+) cells and perforin-1(+) cells, but increased regulatory T cells and M2-like macrophages in EBV/dMLH1 subtype of gastric cancer. LAG-3 was a poor prognostic factor and might be a potential immunotherapeutic target in EBV-positive and MLH1-defective gastric cancer.