Clinical significance of programmed death 1 ligand-1 (CD274/PD-L1) and intra-tumoral CD8+ T-cell infiltration in stage II-III colorectal cancer

Abstract

Programmed cell death-1 (PDCD1/PD-1) and its ligand programmed cell death 1 ligand 1 (CD274/PD-L1) have been reported to suppress anti-tumor T cell-mediated immune responses. However, the clinical significance of CD274 in colorectal cancer were still elusive. We aim to clarify the relationships between CD8+ intratumor-infiltrating lymphocytes (TILs) and CD274 as well as their prognostic values in stage II-III colon carcinoma. Tumor differentiation, perineural invasion (PNI), pN stage and DNA mismatch repair (MMR)-deficient were clearly correlated with CD8+ TILs counts within the tumor microenvironment (p < 0.0001). Furthermore, tumor differentiation and PNI were suggestively correlated with tumor CD274 expression (p = 0.02 and p = 0.0195). Tumor CD274 level was significantly correlated with higher CD8+ TILs (p < 0.0001) but was not associated with MMR-deficient status (p = 0.14). High tumor CD274 expression [hazard ratio (HR) = 2.16, 95% CI = 1.63-2.86, p < 0.0001] and CD8+ TILs [HR = 1.51, 95% CI = 1.19-1.91, p = 0.0007] were associated with improved disease-free survival and overall survival. Additionally, the subgroup of patients who had a high CD8+ TILs/tumor CD274 have better survival outcomes compared with other subgroups (71% vs 53%; p < 0.0001). Therefore, the CD8+ TILs counts and tumor CD274 may be prognostic factors to predict survival and therapeutic responses in stage II-III colon carcinoma patients.

Figure 1

Expression patterns of tumor CD274 (PD-L1) within the tumor microenvironment of colon carcinoma. (A) Negative CD274 immunohistochemical staining within the tumor microenvironment. (B) Weak cytoplasmic CD274 expression. (C) Strong positive cytoplasmic CD274 expression. (D) Weak cytoplasmic and positive membranous CD274 expression in patients with adenocarcinoma. (E) Moderate positive CD274 expression with a membranous pattern. (F) Strong tumor membranous CD274 expression surrounding high CD274-positive inflammatory cells. Scale bar = 50 μm.

Figure 2

Intra-tumoral CD8+ TILs within the tumor microenvironment of colon carcinoma. (A) Low intra-tumoral CD8+ TILs immunohistochemical staining within the tumor microenvironment. (B) High intra-tumoral CD8+ TILs immunohistochemical staining within the tumor microenvironment.

Figure 3

The association of CD8+ TILs and tumor CD274 level in disease-free survival (DFS) among stage II-III colon carcinoma. (A) Stage II-III colon carcinoma patients with high tumor CD274 level within the tumor microenvironment had better 5-year DFS (n = 864, p = 0.0006). (B) High tumor CD274 level in stage II-III MMR-proficient colon carcinoma patients within the tumor microenvironment had improved 5-year DFS (n = 794, p = 0.0006). (C) In stage II-III MMR-deficient colon carcinoma patients, patients with high tumor CD274 level have no association with 5-year DFS (n = 68, p = 0.3298). (D) Stage II-III colon carcinoma patients with high density of CD8+ TILs had better 5-year DFS (n = 867, p < 0.0001). (E) High density of CD8+ TILs in stage II-III MMR-proficient colon carcinoma patients within the tumor microenvironment had improved 5-year DFS (n = 795, p < 0.0001). (F) In stage II-III MMR-deficient colon carcinoma patients, patients with high CD8+ TILs have no association with 5-year DFS (n = 68, p = 0.7552).