Mismatch repair–deficient colorectal cancer: a model of immunogenic and immune cell–rich tumor despite nonsignificant PD-L1 expression in tumor cells

Publication date: Available online 5 December 2017
Source:Human Pathology
Author(s): Glen Le Flahec, Bogdan Badic, Briac Guibourg, Laurent Doucet, Jean-Pierre Bail, Pascale Marcorelles, Ulrike Schick, Arnaud Uguen
Mismatch repair–deficient colorectal cancers (CRC) 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 mismatch repair–deficient (dMMR) CRC as a model of good responders to immunotherapy. We examined 35 dMMR and 34 mismatch repair–proficient (pMMR) CRC using immune cell markers (CD3, CD4, CD8, CD20, CD68, and FOXP3) as well as PD-1 and PD-L1 immunohistochemistry staining in whole tumor specimens and tissue microarray slides to compare 4r PD-L1 immunohistochemistry clones (SP142, E1L3N, 22C3, and 28.8). We observed no significant difference in PD-L1 expression between dMMR and pMMR CRC. 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 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.



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