Heterogeneity of PD-L1 expression and CD8 lymphocyte infiltration in metastatic colorectal cancer and their prognostic significance

Purpose: In recent years, immune checkpoint inhibitors have become a major therapeutic method for the treatment of metastatic colorectal cancer (mCRC). Growing evidence indicates that tumour-infiltrating lymphocytes (TILs) in the tumour microenvironment are a prerequisite for the effectiveness of PD-1/PD-L1 blockade therapy. In this study, we aimed to compare PD-L1 expression and cluster of differentiation 4 (CD4) and CD8 TIL infiltration in primary tumours and paired metastases. Patients and methods: Altogether, 111 patients with mCRC who underwent surgery at our hospital were included. PD-L1, CD4, and CD8 expression were detected by immunohistochemistry in a tissue microarray. PD-L1 expression was assessed using the combined positivity score (CPS), and a score >= 1 was judged as positive. The area proportion of TILs with positive staining >= 10% was classified as "high", while <10% was classified as "low". Results: We observed the discordance of PD-L1 expression between primary tumours and paired metastases in 35/111 (31.5%) patients (kappa = 0.137, P = 0.142). This heterogeneity was signifi-cantly correlated with discordance of CD8 TIL infiltration between primary tumours and paired metastases (P = 0.003). Compared with corresponding colorectal cancer tumours, lung metas-tases showed more CD8 TIL infiltration (P = 0.022, median: 8.5% vs. 5.0%), whereas liver me-tastases exhibited less CD8 TIL infiltration (P = 0.028, median: 3.0% vs. 5.0%). Area proportion of CD4+ and CD8+ TIL infiltration in lung metastases were all higher than those in liver metas-tases (P = 0.005, median: 15.0% vs. 9.0%; P = 0.001, median: 8.5% vs. 3.0%). Compared with p MMR (MSI-L/MS-S) subgroup, area proportion of CD8 TIL infiltration in primary tumours and CD4, CD8 TIL infiltration in paired metastases were all higher in d MMR (MSI-H) group (P = 0.026, median: 15.0% vs 5.0%; P = 0.039, median: 15.0% vs 9.0%; P = 0.015, median: 15.0% vs 5.0%). Preoperative chemo/radiotherapy may increase CD8 TIL infiltration in primary tumours (P = 0.045, median: 10.0% vs. 5.0%). CD8 TIL infiltration in primary tumours was an inde-pendent predictive factor for overall survival (HR 0.28, 95% CI 0.09-0.93, P = 0.038). Conclusion: Heterogeneity in PD-L1 expression and CD8 TIL infiltration was found between pri-mary tumours and paired metastases in mCRC. CD8 TIL infiltration in primary tumours could independently forecast the overall survival of patients with mCRC.