The relationship between the PD-1/PD-L1 pathway and DNA mismatch repair in cervical cancer and its clinical significance

Abstract

BackgroundAccording to recent clinical observations, deficient DNA mismatch repair (dMMR) is capable of improving antitumor effects of the PD-1/PD-L1 pathway, suggesting that dMMR may act as a prognostic indicator of PD-1/PD-L1 antibody drugs. In this study, we examined the dMMR and PD-1/PD-L1 expression, as well as explored the correlation of dMMR status with PD-1/PD-L1 expression in cervical cancer patients, in order to optimize cervical cancer patient selection for PD-1/PD-L1 antibody drug treatment, which is helpful to avoid adverse effects and keep costs manageable.MethodsSixty-six tissue samples from patients with squamous cell carcinoma were collected, and data of their clinical characteristics were also gathered. Based on these samples, the expression levels of MLH1, MSH2, and PD-L1 in cancer cells were tested by immunohistochemical assay (IHC). Moreover, PD-1/PD-L1 expression in tumor-invading lymphocytes (TILs) was detected by IHC as well. Six single-nucleotide-repeat markers of microsatellite instability (MSI), including NR-27, MONO-27, BAT-25, NR-24, NR-21, and BAT-26, were tested by capillary electrophoresis sequencer analysis. According to expression of MLH1, MSH2 and the MSI test, all 66 cases were divided into dMMR or proficient DNA mismatch repair (pMMR) groups. The comparisons of dMMR and PD-L1 in cancer cells and of PD-1/PD-L1 in TILs were conducted categorized by age, childbearing history, history of abortion, ethnicity, and cancer cell differentiation subgroup. Furthermore, PD-L1 levels in cancer cells and PD-1/PD-L1 in TILs were analyzed and compared in both dMMR and pMMR subgroups.ResultsOf the patient samples, 25.8% were associated with dMMR. PD-L1 in cancer cells, PD-L1 in TILs, and PD-1 in TILs took up 59.1%, 47.0%, and 60.6%, respectively. The data indicated that both dMMR and PD-L1 overexpression resulted from lower cancer differentiation, more incidences of childbearing, and a history of abortion. Abortion could significantly increase PD-1 expression levels in TILs. Additionally, more incidence of childbearing or older age (35–55 years) was able to upregulate PD-L1 expression in TILs. Statistical difference of PD-L1 in cancer cells could be observed between dMMR and pMMR subgroups. In the dMMR group, PD-L1 in cancer cells and PD-1 in TILs had no correlation (rs=0.161, p=0.537), but in the pMMR group, they had good correlation (rs=0.645, p<0.001).ConclusionAccording to prior studies and our own experiments, PD-L1 in both cancer cells and TILs and PD-1 in TILs are widely observed in cervical cancer patients, indicating that there may be potential to apply PD-1/PD-L1 antibody drugs in cervical cancer. dMMR patients are associated with higher PD-L1 expression compared with pMMR ones, which suggested that PD-1/PD-L1 antibody drugs may work well in dMMR cervical cancer patients. Moreover, in patients with more incidences of childbearing or abortion, dMMR may be a molecular detection target for clinical application of PD-1/PD-L1 antibody drugs.

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

“…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.…”

“…One explanation for this is that such tumours harbour a higher tumour‐specific neoantigen load that stimulates recruitment of tumour‐infiltrating lymphocytes, leading to overexpression of immune checkpoints such as PD‐1 and PD‐L1. Among tumours with a high mutational burden, those with mismatch repair (MMR) deficiency are associated with higher PD‐L1 expression …”

“…Among tumours with a high mutational burden, those with mismatch repair (MMR) deficiency are associated with higher PD-L1 expression. [13][14][15][16] PD-L1 expression by tumour cells and/or tumourinfiltrating lymphocytes (TILs) and/or tumour-associated macrophages has been reported in several lower genital tract neoplasms, including cervical and vulvar squamous cell carcinoma, 13,[17][18][19][20] cervical squamous intraepithelial lesions, 20 cervical adenosquamous carcinoma 18 and endocervical adenocarcinoma. 18,19 A case of a PD-L1 negative SmCC-Cx with complete response to nivolumab (anti PD-1 therapeutic agent) was reported recently.…”

The Preventive Effect of Dietary Antioxidants against Cervical Cancer versus the Promotive Effect of Tobacco Smoking

“…In addition, tobacco smoking can inhibit the immune system response to HPV, especially the activities of T helper lymphocytes, natural killer cells, and immunoglobulin E [42]. The expression of programmed death-1 (PD-1) is also observed in 47.0%-60.8% of cervical cancer patients [43][44][45]. Furthermore, active tobacco smoking or a history of tobacco smoking during radiation therapy for cervical cancer is associated with unfavorable disease-free and overall survival outcomes [46].…”

Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Future Directions

“…PD-L1 is expressed on the surface of cervical cancer tumor cells, antigen-presenting cells and tumor-infiltrating lymphocytes (TILs), whereas most PD-1-positive cells have been identified as T cells in the stroma of cervical cancer. PD-1 expression in the tumor stroma of cervical cancer is observed in 46.9%~60.8% of patients [13,14]. Various researchers have also investigated PD-L1 expression in cervical cancer tissue.…”