Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer

Abstract

In recent years, it has become evident that tumor cells have immune escape mechanisms, and immune checkpoint inhibitor therapy (anti-PD-1/PD-L1 antibody) has shown benefit in various cancers. In endometrial tumors with microsatellite-instability (MSI), somatic mutations have the potential to encode ‘’non-self’’ immunogenic antigens, and lymphocytes have been shown to infiltrate the tumor. Therefore, immune checkpoint inhibitor therapy might be effective in endometrial cancers with MSI. Expression of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), the presence of tumor-infiltrating lymphocytes (CD8+), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 149 patients with endometrial cancer. We examined whether tumors with MSI had an enhanced immune microenvironment and whether MSI could be a predictor of the therapeutic effect of PD-1/PD-L1 immunotherapy in endometrial cancer. Loss of MMR protein expression was identified in 42 (28.2%) of 149 patients (MSI group) with endometrial cancer. There was no significant relationship between MSI status and age (p = 0.193), histological grade (p = 0.097), FIGO stage (p = 0.508), pelvic lymph node metastasis (p = 0.139), or depth of myometrial invasion (p = 0.494). However, the presence of tumor-infiltrating lymphocytes (CD8+) and PD-L1/PD-1 expression were significantly higher in the MSI group compared to the microsatellite-stable group (p = 0.002, p = 0.001, and p = 0.008, respectively). These results suggest that immune checkpoint inhibitors (anti-PD-1/PD-L1 antibody) could be effective in endometrial cancers with MSI. The presence of MSI may be a biomarker for good response to PD-1/PD-L1 immunotherapy in endometrial cancer.

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

“…14 In a recent study of endometrial cancer, the presence of TILs (CD8 + ) and PD-L1/PD-1 expression were significantly higher in dMMR group compared to the MSS group, suggesting that immune checkpoint inhibitors could be effective in endometrial cancers with MSI. 26 Supporting the hypothesis of immune evasion, dMMR ovarian carcinomas showed significantly increased CD3 + /CD8 + TILs and PD-L1 expression in intratumoral immune cells compared to MMR-proficient ovarian cancers. 8 This is concordant with our results, which show higher PD-L1 expression levels as well as increased CD3 + TILs and PD-L1 + TILs in tumours with MLH1/ PMS2 loss, with a statistically significant correlation between higher PD-L1 score and MLH1/PMS2 loss.…”

“…We also found an association between higher PD-L1 expression levels and aberrant MMR expression. Similarly, other gynaecological tumours with dMMR/microsatelliteinstability (MSI) have been found to be associated with higher PD-1 and/or PD-L1 expression compared with tumours with normal MMR expression/microsatellite stability, such as cervical cancers, 13 endometrial cancers 16,26,27 and clear cell ovarian cancers with MSI. 15 In contrast, MMR status did not correlate significantly with PD-L1 expression in tumours such as clear cell carcinoma of the ovary and endometrium in one study.…”

“…In endometrial carcinoma, ultramutated (POLE mutated) and hypermutated (microsatellite unstable, dMMR) tumours have higher CD3 + /CD8 + TILs and overexpression of PD‐1 and PD‐L1 in TILs and peritumoral lymphocytes, compared with microsatellite‐stable (MSS) tumours; however, PD‐L1 expression in tumour cells is infrequent . In a recent study of endometrial cancer, the presence of TILs (CD8 + ) and PD‐L1/PD‐1 expression were significantly higher in dMMR group compared to the MSS group, suggesting that immune checkpoint inhibitors could be effective in endometrial cancers with MSI . Supporting the hypothesis of immune evasion, dMMR ovarian carcinomas showed significantly increased CD3 + /CD8 + TILs and PD‐L1 expression in intratumoral immune cells compared to MMR‐proficient ovarian cancers .…”

The Case for Proteomics and Phospho‐Proteomics in Personalized Cancer Medicine

“…In 2017 the FDA approved pembrolizumab for the treatment of any unresectable or metastatic solid tumor with microsatellite instability . This was the first time that a cancer drug was introduced based on genetics rather than tumor site or tissue type.…”

Gene Promoter Methylation in Endometrial Carcinogenesis

“…The presence of MSI caused by mismatch repair deficiency either through gene promoter methylation or gene mutation seems clinically relevant. A strong relation between the expression of the programmed cell death 1 protein (PD-1) and programmed cell death 1 ligand 1 (PD-L1) as well as tumour-infiltrating lymphocytes (CD8+) and MSI was recently demonstrated [ 35 , 36 ]. This might indicate that immune checkpoint inhibitors (anti-PD-1/PD-L1 antibody) could be effective in endometrial cancers with MSI.…”