Combined prognostic value of CD274 (PD-L1)/PDCDI (PD-1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status

The CD274 (programmed cell death ligand-1, PD-L1)/PDCD1 (programmed cell death-1, PD-1) pathway is crucial suppressor of the cytotoxic immune response. Antibodies targeting CD274 or PDCD1 have been revealed to be effective in several malignancies. In colorectal cancer, the response to CD274/PDCD1 blockage is associated with microsatellite instability. However, the value of CD274/PDCD1 for predicting response to treatment or survival benefit is still unclear. The aims of the study were (1) to clarify differences in immune microenvironment and expression of checkpoint proteins (CD274/PDCD1) in DNA mismatch repair-proficient, mismatch repair-deficient, and hereditary Lynch syndrome-associated colorectal cancer, and (2) to assess the prognostic value of these factors and their combinations. Ninety-four mismatch repair-deficient colorectal cancers, 100 age, sex, and AJCC/UICC stage-matched mismatch repair-proficient colorectal cancers, and 48 Lynch syndrome-associated colorectal cancers were analyzed. Using whole section samples, detailed analysis of immune cell score, PDCD1, and CD274 expression was performed. Overlapping of CD274 expression in tumor and immune cells was almost complete (95%). Immune cell score and CD274/PDCD1 positivity were significantly more frequent in mismatch repair-deficient than in mismatch repair-proficient colorectal cancers (70% vs. 41% (high immune cell score); 81% vs. 49% (PDCD1(high)), 23% vs. 1% (CD274 on tumor cells) and 68% vs. 30% (CD274 on immune cells), P < 0.001), and were associated strongly with each other. Although the independent impact of immune cell score, PDCD1, and CD274 on immune cells was moderate, the immunoprofile parameter combining the above three factors appeared to be a strong independent prognostic factor for disease-specific survival and overall survival (P = 0.001) and had suggestive impact on disease-free survival (P = 0.011). Our results encourage the use of immune cell score analysis together with PDCD1 and CD274 detection to improve the prognostic evaluation of colorectal cancer patients. Particularly, the analyses from whole tissue sections are encouraged to allow reliable and cell-specific analyses of CD274 expression.