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

Abstract

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 (n = 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and MLH1 methylation testing. Those found to have MLH1 hypermethylation formed the sporadic MMR-deficient group (n = 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group (n = 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+ (p = <0.0001), CD8+ (p = <0.0001), CD45RO+ (<0.0001), FoxP3+ (p = <0.0001), and PD1+ (p = <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ (p = 0.02), CD45RO+ (p = 0.007), and PD-1+ (p = 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient Ramchander et al.Immune Landscape of Endometrial Tumors 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.

Immune Checkpoint Inhibitors: A Promising Choice for Endometrial Cancer Patients?

“…However, there was no stratification of MSI-H EC tumors according to their sporadic or inherited Lynch syndrome (LS) origins. Since MSI-H tumors display an increased immunogenicity compared with MSS tumors, some authors have investigated differences in immune cell populations between sporadic and LS MSI-H endometrial cancer, showing that these two groups are distinct immunological entities with different types of immune cells in stroma and tumor, respectively [ 65 , 66 ]. In conclusion, given the evident benefit found in MSI-H/MMRd cancer patients treated with immune checkpoint inhibitors, all EC patients should be tested to define the MMR status at the time of diagnosis, including the immune-infiltrate and the expression of PD-1 and PD-L1, in order to establish their future eligibility for immunotherapy treatment [ 67 , 68 ].…”

Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

“…These interact with activated T-lymphocytes and thereby trigger a potentially strong antitumor immune response in the tissue. Accordingly, recent studies found LS EC to be highly immunogenic [ 123 , 124 ].…”

Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

“…Similarly, Ramchander et al reported a significantly elevated number of CD8-positive T cells in the invasive margin of LS-associated MSI ECs compared to sporadic cases. The same tendency was observed in the tumor center but failed to reach statistical significance [53]. Furthermore, another study reported a higher frequency of PD-L1 expression in LS-associated MSI ECs, compared to sporadic MSI ECs [65].…”

“…We first compared the immune infiltration determined by the quantitative analysis of different immune markers (CD3, CD4, CD8, PD1, PD-L1, FoxP3, CD45) between hereditary and sporadic MSI cancers. Seven studies [47][48][49][50][51][52][53] were informative for quantitatively evaluating the extent of local immune infiltration in MSI CRCs (Table 1). We looked at the results from the immunohistochemical analysis of different T cell subsets of these studies, where a total of 122 hereditary MSI CRC and 145 sporadic MSI CRC samples were examined.…”