Characterization of LAG-3, CTLA-4, and CD8 + TIL density and their joint influence on the prognosis of patients with esophageal squamous cell carcinoma.

Background: We aimed to characterize the relationships of lymphocyte activation gene-3 (LAG-3) expression, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expression, and CD8(+) tumor-infiltrating lymphocyte (TIL) density, and to investigate the joint prognostic impact of these three markers in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Methods: Expression of LAG-3, CTLA-4 and the density of CD8(+) TILs were evaluated by immunohistochemistry in resected ESCC. The associations between LAG-3 expression and clinicopathologic characteristics, as well as patient prognoses, were analyzed. Results: A total of 183 patients were included. LAG-3 expression was observed in 69 (37.7%) patients. Positive LAG-3 expression was significantly associated with CTLA-4 expression (P=0.004). LAG-3 positivity, CTLA-4 positivity, and low CD8(+) TIL densities were significantly associated with worsening recurrence-free survival (RFS) [LAG-3: hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.10-2.89; P=0.019; CTLA-4: HR, 1.69; 95% CI, 1.04-2.73; P=0.033; CD8(+): HR, 0.60; 95% CI, 0.38-0.94; P=0.025] and overall survival (OS) (LAG-3: HR, 2.09; 95% CI, 1.24-3.53; P=0.006; CD8(+): HR, 0.56; 95% CI, 0.33-0.95; P=0.032). Subgroup analysis revealed that the LAG-3(-)CTLA-4(-)CD8(+) group had the best RFS (P<0.001) and OS (P<0.001). Conclusions: LAG-3 expression was correlated with CTLA-4 expression on TILs. Positive LAG-3 expression was associated with poor prognoses in ESCC. A combination of LAG-3, CTLA-4 expression and CD8(+) TILs density could further stratify patients into different subgroups with distinct prognoses.