PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas

Zhang, Shuang; Minaguchi, Takeo; Xu, Chenyang; Qi, Nan; Itagaki, Hiroko; Shikama, Ayumi; Tasaka, Nobutaka; Akiyama, Azusa; Sakurai, Minoru; Ochi, Hiroki

doi:10.1186/s12885-020-6545-9

Cited by 27 publications

(38 citation statements)

References 41 publications

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“…However, there were some discrepancies in the prognostic value of PD-L1 for endometrial carcinoma in previous studies. Zhang et al, 2020 [31] reported that high PD-L1 in TCs was associated with better overall survival, while high PD-L1 in TICs was associated with worse overall survival. In contrast, Engerud et al, 2020 [32] reported that PD-L1 expression in tumour cells was significantly associated with higher grade tumours, with no association with overall survival.…”

Section: Discussionmentioning

confidence: 99%

Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

et al. 2020

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Endometrial carcinoma is the only gynaecologic malignancy with a raising incidence and mortality, posing a major health concern worldwide. The upregulation of programmed death ligand 1 (PD-L1) on tumour cells causes T-cell suppression, which impedes antitumour immunity, promotes immune cell evasion and enhances tumour survival. The aim of this study was to evaluate PD-L1 expression in endometrial carcinoma and to correlate it with survival rate. A total of 59 cases of endometrial carcinoma were evaluated. Thirty-two cases of non-neoplastic endometrial tissue were included as control. PD-L1 immunohistochemistry was performed on all cases. PD-L1 expression was evaluated on tumour cells and immune cells. PD-L1 was positive in 62.7% (37/59) and 28.8% (17/59) of immune cells and tumour cells, respectively. PD-L1 expression in immune cells was significantly higher in endometrial carcinoma than in non-neoplastic endometrium (p < 0.001). Among the patients with endometrial carcinoma, PD-L1 expression in tumour cells was significantly higher in patients who died (10/15, 66.7%) compared to those who survived (7/44, 15.9%) (p < 0.001). It is noteworthy to point out that the expression of PD-L1 in tumour cells was significantly associated with a poor survival. This suggests that immunomodulation using PD-L1 inhibitors may be useful in advanced endometrial carcinoma.

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Section: Discussionmentioning

confidence: 99%

Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

et al. 2020

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“…Importantly, EC was found to have the highest prevalence of MSI of 30 tumor types. About 30% of primary EC are MSI-H, whereas 13% to 30% of recurrent EC are MSI-H or MMRd [39,[46][47][48][49].…”

Section: Cellular and Molecular Regulation Of Endometrial Cancer Progmentioning

confidence: 99%

“…One report showed that POLE-ultramutated and MSI-H EC tumors also have an overexpression of PD-L1 [46]. Interestingly, there is still great debate concerning the interpretation and relevance of PD-L1 expression on immune or tumor cells across several tumor types and its relationship to ICI efficacy in cancer [55].…”

Section: Cellular and Molecular Regulation Of Endometrial Cancer Progmentioning

confidence: 99%

“…Interestingly, there is still great debate concerning the interpretation and relevance of PD-L1 expression on immune or tumor cells across several tumor types and its relationship to ICI efficacy in cancer [55]. However, it is believed that tumors such as EC, with elevated TIL numbers and high tumor mutational burden, are more easily recognized and targeted by T cells [39,46,47,56,57]. Such tumors typically respond well to ICI therapy [58], with patients showing significant disease improvement and improved overall survival (O/S), as is often the case for EC patients selected for ICI therapy.…”

Section: Cellular and Molecular Regulation Of Endometrial Cancer Progmentioning

confidence: 99%

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Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

Drakes

Czerlanis

Stiff

2020

Cancers

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This review provides an update on the current use of immune checkpoint inhibitors (ICI) in female gynecologic cancers, and it addresses the potential of these agents to provide therapy options for disease management and long-term remission in advanced disease patients, where surgery, chemotherapy, and/or radiation fail to meet this goal. The topic of immune checkpoint inhibitors (ICI) blocking cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed death-1 (PD-1) axis has come to the forefront of translational medicine over the last decade for several malignancies. The text will focus primarily on a discussion of ovarian cancer, which is the most frequent cause of death of gynecologic cancers; endometrial cancer, which is the most often diagnosed gynecologic cancer; and cervical cancer, which is the third most common female gynecologic malignancy, all of which unfavorably alter the lives of many women. We will address the critical factors that regulate the outcome of these cancer types to ICI therapy, the ongoing clinical trials in this area, as well as the adverse immune responses that impact the outcome of patients given ICI regimens.

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“…The fraction of ECs that are positive for PD-L1 expression varied from 14 to 59% (Mo et al, 2016;Li et al, 2018;Engerud et al, 2020). Although it was reported that PD-L1 expression has no significant impact on patient survival (Engerud et al, 2020), recent studies presented contrary results showing that higher PD-L1 expression in EC samples was associated with improved survival (Yamashita et al, 2017;Liu et al, 2019;Zhang et al, 2020). Also, increased PD-L1 expression in EC cells was significantly correlated with well-differentiated histology and a lower risk of myometrial invasion and lymphatic spread (Zhang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3

Dong

Xiong

et al. 2020

Front. Cell Dev. Biol.

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BackgroundPoorly differentiated endometrioid adenocarcinoma and serous adenocarcinoma represent an aggressive subtype of endometrial cancer (EC). Programmed death-ligand-1 (PD-L1) was known to exhibit a tumor cell-intrinsic function in mediating immune-independent tumor progression. However, the functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown.MethodsPD-L1 expression in 65 EC tissues and 18 normal endometrium samples was analyzed using immunohistochemical staining. The effects of PD-L1 on aggressive EC cell growth, migration and invasion were investigated by cell functional assays. Luciferase reporter assays were used to reveal the microRNA-216a (miR-216a)-dependent mechanism modulating the expression of PD-L1.ResultsPositive PD-L1 expression was identified in 84% of benign cases but only in 12% of the EC samples, and the staining levels of PD-L1 in EC tissues were significantly lower than those in the normal tissues. Higher PD-L1 expression predicts favorable survival in EC. Ectopic expression of PD-L1 in aggressive EC cells results in decreased cell proliferation and the loss of mesenchymal phenotypes. Mechanistically, PD-L1 exerts the anti-tumor effects by downregulating MCL-1 expression. We found that PD-L1 levels in aggressive EC cells are regulated by miR-216a, which directly targets PD-L1. We further identified a mechanism whereby the long non-coding RNA MEG3 represses the expression of miR-216a, thereby leading to increased PD-L1 expression and significant inhibition of cell migration and invasion.ConclusionThese results reveal an unappreciated tumor cell-intrinsic role for PD-L1 as a tumor suppressor in aggressive EC cells, and identify MEG3 and miR-216a as upstream regulators of PD-L1.

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PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas

Cited by 27 publications

References 41 publications

Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3

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