title: PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinomas, Including Lynch Syndrome-associated and MLH1 Promoter Hypermethylated Tumors.
abstract: Mismatch repair (MMR)-deficient endometrial carcinomas (ECs) bearing Lynch syndrome (LS)-associated germline mutations or sporadic MLH1 promoter hypermethylation (MLH1hm) are highly immunogenic and may represent excellent candidates for therapies targeting the programmed cell death (PD)/programmed cell death ligand-1 (PD-L1) immune checkpoint pathway. This study evaluates PD-L1 expression in MMR-deficient ECs including LS-associated and MLH1hm cases, in comparison with MMR-intact tumors. Immunohistochemistry for PD-L1/CD274 was performed on 38 MMR-deficient and 29 MMR-intact ECs. Staining was scored in the tumor and the peritumoral immune compartment. The majority of MMR-deficient tumors were PD-L1 positive (53%) in at least a subset of tumor cells. LS-associated tumors were more likely to be PD-L1 positive relative to MLH1hm tumors (70% vs. 33%, P=0.05). Only 10% of MMR-intact ECs demonstrated any tumoral PD-L1 expression; this was significantly lower than was observed in MMR-deficient tumors (P=0.0005). When reviewed by histologic grade, PD-L1 expression remained highest in LS-associated ECs followed by MLH1hm and MMR-intact carcinomas, respectively. The MMR immunohistochemical pattern most uniformly associated with PD-L1 expression was MSH6 loss. Immune PD-L1 expression was seen in 100% of MMR-deficient and 66% of MMR-intact cases. This study represents the first to characterize differences in PD-L1 expression between LS-associated and MLH1hm endometrial cancers. It demonstrates that tumoral PD-L1 expression is more common in LS-associated endometrial cancers relative to MLH1hm and MMR-intact tumors, although sporadic cancers often show PD-L1 positive immune staining. These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects.
authors.affiliation: Departments of *Pathology †Gynecologic Oncology, University of Virginia, Charlottesville, VA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Sloan
authors.forename: Kari L
authors.initials: KL
authors.lastname: Ring
authors.forename: Brian C
authors.initials: BC
authors.lastname: Willis
authors.forename: Susan C
authors.initials: SC
authors.lastname: Modesitt
authors.forename: Anne M
authors.initials: AM
authors.lastname: Mills
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C501486:MLH1 protein, human; D000070957:MutL Protein Homolog 1