Mismatch repair–deficient colorectal cancer: a model of immunogenic and immune cell–rich tumor despite nonsignificant programmed cell death ligand-1 expression in tumor cells

Mismatch repair–deficient (dMMR) colorectal cancers (CRCs) are good responders to anti–programmed cell death ligand-1 (PD-L1) immunotherapy, but the value of PD-L1 testing remains unclear. We studied PD-L1 expression and the tumor immune microenvironment in dMMR CRC as a model of good responders to immunotherapy. We examined 35 dMMR and 34 mismatch repair–proficient (pMMR) CRCs using immune cell markers (CD3, CD4, CD8, CD20, CD68, and FOXP3) as well as programmed cell death receptor-1 (PD-1) and PD-L1 immunohistochemistry staining in whole tumor specimens and tissue microarray slides to compare 4 PD-L1 immunohistochemistry clones (SP142, E1L3N, 22C3, and 28.8). We observed no significant difference in PD-L1 expression between dMMR and pMMR CRCs. Only 2 dMMR tumors had membranous PD-L1 staining. Expression of PD-L1 was greater in stromal immune cells of dMMR CRC, which also contained more numerous intraepithelial (CD3+, CD8+, FOXP3+, and PD-1+) and stromal (CD8+, PD-1+) lymphocytes than did pMMR tumors. Immune cell quantification discriminated better between dMMR and pMMR tumors than did PD-L1 expression. Tumor heterogeneity and variations in PD-L1 expression were noted with different antibodies, especially for PD-L1+ immune cells, which were more numerous at the invasion margin. Given the poor correlation with mismatch repair status and technical limitations, the value of PD-L1 testing to accompany the development of anti–PD-1/PD-L1 immunotherapy remains unclear. Further clinical trials are required to determine which parameters are valuable predictive biomarkers of the response to immunotherapy among mismatch repair status, PD-L1 expression, and immune cell quantification in CRC. •We compared 35 mismatch repair–deficient with 34 mismatch repair–proficient colorectal cancers.•We examined programmed cell death ligand-1 (PD-L1) expression and tumor immune environment.•No significant PD-L1 expression was noted in tumor cells.•A significant difference appeared for PD-L1 and programmed cell death receptor-1 expression in stromal immune cells.•Immune cell quantification easily distinguished mismatch repair–deficient from mismatch repair–proficient tumors.