Expression of Immunomodulatory Molecules PD-1, PD-L1, and PD-L2, and their Relationship With Clinicopathologic Characteristics in Endometrial Cancer

Süngü, Nuran; Yıldırım, Melahat; Desdicioğlu, Raziye; Aydoğdu, Özge Başaran; Kılıçarslan, Aydan; Doğan, Hayriye Tatlı; Yazgan, Aylin; Akyol, Mesut; Erdoğan, Fazlı

doi:10.1097/pgp.0000000000000543

Cited by 39 publications

(35 citation statements)

References 21 publications

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“…PD-L1 expression has been shown to be a prognostic marker of prognosis in various cancers, including lung cancer, esophageal squamous cell carcinoma, pancreatic cancer, and colorectal cancer (5)(6)(7)(8). Many studies have also explored the prognostic value of PD-L1 in EC, with conflicting results (9)(10)(11)(12)(13)(14)(15)(16)(17). Some investigators have reported that elevated PD-L1 expression is associated with shorter survival (16).…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Lü¹,

Li²,

Luo³

et al. 2020

Front. Oncol.

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Background: A series of studies have explored the prognostic value of programmed death-ligand 1 (PD-L1) in patients with endometrial cancer (EC); however, the results are controversial. Therefore, this meta-analysis was performed to estimate the associations between PD-L1 expression and the prognosis and clinicopathological features of EC. Methods: A comprehensive literature search of PubMed, Web of Science, and Embase was conducted up until September 06, 2019. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were computed using the random-effects model (REM) or fixed-effects model (FEM). Odds ratios (ORs) and 95% CIs were calculated to evaluate the relationship between PD-L1 and clinicopathological factors. Results: A total of 9 studies with 1,615 patients were included in the meta-analysis. The combined data showed that high expression of PD-L1 was not significantly correlated with OS (HR = 1.20, 95% CI = 0.41-3.52, p = 0.737) or PFS (HR = 1.12, 95% CI = 0.50-2.54, p = 0.778) in EC. In addition, PD-L1 expression was significantly associated with poor differentiation (OR = 2.82, 95% CI = 1.96-4.06, P < 0.001) and advanced stage (OR = 1.71, 95% CI = 1.12-2.60, p = 0.013). Conclusion: This meta-analysis suggests that PD-L1 expression is not associated with poor prognosis in patients with EC. However, PD-L1 expression is positively correlated with poor differentiation and advanced tumor stage in EC.

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Section: Introductionmentioning

confidence: 99%

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Lü¹,

Li²,

Luo³

et al. 2020

Front. Oncol.

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“…PD-L2 expression was evaluated in type II ECs in 12 patients and 7 (58,3%) were positive for PD-L2 without a significant difference among patients with different ages, differentiation status, clinical stages, histological types, or status of vascular invasion in the tumor (23). Additionally, as reported by Sung and collaborators, analyzing 127 EC tumor specimens (113 classified as type I), PD-L2 expression seems to differ from PD-L1 with PD-L1 positive staining in tumor cells at 36.2% and 64.4% with PD-L2 (24). In previous works, no significant differences in PD-L2 expression have been found between normal endometrium and type I tumor (23,25,26).…”

Section: Discussionmentioning

confidence: 54%

Biological Function of PD-L2 and Correlation With Overall Survival in Type II Endometrial Cancer

et al. 2020

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In cancer, upregulation of coinhibitory B7 ligands has been associated with immune evasion. So far, anti-programmed death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) antibodies have been used in immuno-oncology, with promising outcomes; however, it is still needed to identify other markers, especially for endometrial cancer (EC). EC is a gynecological malignancy historically classified into two types: type I, with mostly estrogen-dependent endometrioid diseases, and the most aggressive type II, including mainly estrogen-independent and non-endometrioid tumors. PD ligand-2 (PD-L2) is known as the second ligand of the PD-1 receptor and, upon its binding, contributes to T-cell exhaustion. Up to now, very few information are available about PD-L2 in cancers, and no data have been reported for EC. The aim of this work was to characterize the PD-L1 and PD-L2 ligand expression profile in EC cell lines, focusing the attention on the biological role of PD-L2 and its prognostic impact in human type II EC biopsies. Using in silico analysis of TCGA data, we performed a molecular profiling in a cohort of 506 patients, both types I and II, and PD-1 ligands expression was also analyzed in different primary human EC cell lines. Moreover, PD-L2 staining was evaluated in a cohort of human type II EC samples and correlated with the overall survival (OS), progression-free survival (PFS), and additional clinicopathological data. From the in silico analysis, PD-L2 was more expressed than PD-L1 in EC cell lines. PD-L2 was found highly expressed in 64.44% of tumor specimens, predominantly in the serous subtype, in both stromal and epithelial components, while in peritumoral and normal tissues it was predominantly moderate or low. In vitro, we investigated the cell autonomous role of PD-L2 in controlling cell survival, migration, and chemoresistance.

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“…Moreover, 14.3% of healthy endometrial tissues and 17.3% of EA tissues were positive for PD-L1 expression, while 20.0% of healthy endometrial tissues and 37.3% of EA tissues were positive for PD-L2 expression [88]. Sungu et al found positive staining for PD-L1 (36%), PD-L2 (64.4%), and PD-1 expression (61.6%) in EA cells, and positive PD-L1 (36.2%) and PD-L2 (93.2%) expression in immune cells [89]. Collectively, the findings show that the synergism between PD-1, PD-L1, and PD-L2 could be a possible target for immunotherapy in advanced EA.…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

Kooshkaki

Derakhshani

Safarpour

et al. 2020

IJMS

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Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

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Expression of Immunomodulatory Molecules PD-1, PD-L1, and PD-L2, and their Relationship With Clinicopathologic Characteristics in Endometrial Cancer

Cited by 39 publications

References 21 publications

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Biological Function of PD-L2 and Correlation With Overall Survival in Type II Endometrial Cancer

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

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