PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinoma and Tumor-associated Immune Cells: Differences Between MLH1 Methylated and Nonmethylated Subgroups

Abstract

Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n = 37) and 66.5% (n = 117) of cases, respectively, and with a 5% cutoff in 5.1% (n = 9) and 39.8% (n = 70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR) = 5.236, 95% confidence interval (CI) = 2.075-13.211, P = 0.001, and OR = 3.702, 95% CI = 1.759-7.791, P = 0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR = 5.104, 95% CI = 1.876-13.881, P = 0.001, and for 5% cutoff: OR = 3.322, 95% CI = 1.540-7.166, P = 0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR = 6.102, 95% CI = 1.280-10.096, P = 0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR = 6.757, 95% CI = 1.569-29.109, P = 0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor

Exploring the expression and the prognosis of mismatch repair protein and PD-L1 in colorectal cancer

“…The reason for this may be due to the homology of MLH1 and PMS2, which can form functionally paired dimers and cause degradation of the corresponding paired dimers when one of them is mutated, similar to MSH2 and MSH6 [21,22] . Further analysis in this study also revealed that PMS2 expression de ciency was also associated with PD-L1 expression (P < 0.05), and Kir et al found that PMS2 de ciency was an independent risk factor for PD-L1 positivity by analyzing 176 resected endometrial cancer specimens [23] similarly, Morgan et al found that PD-L1 was more often seen in dMMR status tumors by analyzing cervical neuroendocrine carcinomas [24] . However, studies related to the relationship between PMS2 and PD-L1 in CRC tumors are rare, and the speci c mechanism of this nding in this paper still needs to be investigated at a deeper level to be discovered, but to a certain extent, it provides research ideas for subsequent researchers.…”

Immunohistochemical expression of PD-L1 and its correlation with microsatellite status in endometrial and ovarian clear cell carcinomas: a cross-sectional study

“…While no association between PD-L1 mRNA expression and OS was found, mRNA expression was significantly correlated with worse progression-free survival (PFS) [27]. In a study in 2021, decreased DFS was observed in endometrial carcinoma cases with immune cell PD-L1 positivity ≥ 5% [28]. In another study, the relationship between PD-L1 expression and prognosis was studied among 120 OCCC patients.…”

Exploring the Expression and Prognosis of Mismatch Repair Proteins and PD-L1 in Colorectal Cancer in a Chinese Cohort

“…27,28 In addition, Kiret al discovered that PMS2 deficiency was an independent risk factor for PD-L1 positivity through analysis of 176 resected endometrial cancer specimens. 29 Further analysis in our study revealed that PMS2 expression deficiency did associate with PD-L1 expression, which was consistent with the above findings (P < 0.05), the reason for this may be due to the situation that, in this study, PMS2 deficiency was the most common type of dMMR (10 in 15), and the larger amount of data makes the association between PMS2 deficiency and PD-L1 positive expression easier to detect compared to the other three proteins. However, studies related to the relationship between PMS2 and PD-L1 in CRC tumors are few, thus more in-depth studies are needed to clarify the mechanisms.…”