Endometrial tumors with MSI-H and dMMR share a similar tumor immune microenvironment

Abstract

Purpose: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are important biomarkers for predicting responses to immune checkpoint inhibitor (ICI) thera-pies. Although PCR-based tests for high MSI (MSI-H) and dMMR yield highly concordant results in endometrial cancer (EC), it is unclear whether this is true for MSI-H and MMR detected by next-generation sequencing (NGS) and immunohistochemistry (IHC), respec-tively. This study investigated whether EC with MSI-H identified by NGS and dMMR identified by IHC have similar tumor immune microenvironments. Patients and Methods: EC tissue and corresponding peripheral blood lymphocyte samples were collected from 99 randomly selected patients. MSI status and tumor mutation burden (TMB) were examined by NGS. MMR protein and programmed death ligand (PD-L)1 expression and tumor-infiltrating lymphocyte (TIL) abundance were evaluated by IHC. Results: Of the 99 EC samples, 29 (29%) had dMMR by IHC, while 18 (18%) had MSI-H by NGS. MSI and MMR status identified by the two methods were discordant in the 99 EC patients, and 2/18 NGS-identified MSI-H patients (11%) retained MMR protein expression. MSI-H and dMMR endometrial tumors had similar numbers of cluster of differentiation (CD)3+ TILs (T cells) and CD8+ TILs (cytotoxic T cells) in the tumor center and periphery, which differed from those in microsatellite stable (MSS) and mismatch repair-proficient (pMMR) EC; they also showed similar TMB, PD-L1 expression, and TIL counts with higher TMB and PD-L1 expression than MSS and pMMR ECs. The abundance of CD3+ and CD8+ TILs was increased in PD-L1-positive EC. Conclusion: NGS-identified MSI status and IHC-identified MMR status were inconsistent in EC, and 11% of NGS-identified MSI-H tumors retained MMR protein expression. Conversely, MSI and MMR status determined by the two methods provided similar data on TMB, PD-L1 expression, and TIL abundance, which can guide treatment decisions with ICIs.