Wenjia Wang1, Donglai Chen2, Yuhuan Zhao1, Ting Zhao1, Junmiao Wen3, Yiming Mao1,4, Chang Chen2, Yonghua Sang1, Yongsheng Zhang5, Yongbing Chen1. 1. Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China. 2. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai 200433, China. 3. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 4. Department of Thoracic Surgery, Suzhou Kowloon Hospital Shanghai Jiaotong University School of Medicine, Suzhou 215028, China. 5. Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Abstract
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; CTLA-4: HR, 1.47; 95% CI, 0.86-2.53; P=0.161; 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. 2019 Annals of Translational Medicine. All rights reserved.
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; CTLA-4: HR, 1.47; 95% CI, 0.86-2.53; P=0.161; 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. 2019 Annals of Translational Medicine. All rights reserved.
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