Journal Article

Distinct Immunological Landscapes Characterize Inherited and Sporadic Mismatch Repair Deficient Endometrial Cancer

Bolton, James, Ramchander, Neal C., Evans, D. G., Harries, Lauren, Ryan, Neil A. J., Bosse, Tjalling, Crosbie, Emma J., Walker, Thomas D. J.

2020

Overview

Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified ( = 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and methylation testing. Those found to have hypermethylation formed the sporadic MMR-deficient group ( = 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group ( = 35). A fully automated monoplex IHC panel was performed on sequential formalin-fixed paraffin-embedded tumor sections to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ immune cells, and PD-L1 expression by tumor/immune cells. Two independent observers quantified immune marker expression at the tumor center and invasive margin. Mean and overall compartmental T-cell counts generated standard (binary: Low/High) and higher resolution (quaternary: 0-25, 25-50, 50-75, 75-100%) immune scores, which were used as explanatory features in neural network, support vector machine, and discriminant predictive modeling. Overall T-cell counts were significantly different between the three cohorts: CD3+ ( = <0.0001), CD8+ ( = <0.0001), CD45RO+ (<0.0001), FoxP3+ ( = <0.0001), and PD1+ ( = <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ ( = 0.02), CD45RO+ ( = 0.007), and PD-1+ ( = 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient tumors, but not between sporadic MMR-deficient and MMR-proficient tumors. Predictive modeling could accurately determine MMR status based on CD8+ T-cell counts within the tumor center alone. This study shows that LS-associated and sporadic MMR-deficient EC are distinct immunological entities, which has important implications for treatment and prognosis.

• Publisher: Frontiers Media S.A
• Subject: endometrial cancer / immune microenvironment / Immunology / Lynch Syndrome / microsatellite instability / mismatch repair / PD-1