Abstract
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.
Highlights
In developed countries, endometrial cancer (EC) is the most commonly diagnosed gynecological malignancy [1]
The expression of PD-ligand 1 (PD-L1) and PD ligand-2 (PD-L2) in normal uterine tissue obtained from a healthy donor and in six EC cell lines, two of which, PCEM004a and PCEM004b, are classified as mixed type I/II, was evaluated by RT-PCR and Western blot analysis
PD-L2 levels were significantly higher in most EC cell lines compared to normal uterus, while PD-L1 was expressed predominantly in both mixed type I/II PCEM004 cell lines but were not significantly different from the control
Summary
Endometrial cancer (EC) is the most commonly diagnosed gynecological malignancy [1]. Non-endometrioid type II EC is less common but associated with an aggressive behavior and comprises only 3 to 10% of ECs but accounting for 39–44% of EC deaths [3]. This group includes different non-endometrioid histological subtypes (e.g., serous or clear cell adenocarcinomas), and it develops from an atrophic endometrium. They are poorly differentiated, aggressive, and associated with a poor prognosis [1, 2]. Regarding EC, the role for PD-1 blockade in POLE-mutated and MSI-high tumors is clear, but for other molecular subtypes of EC, many aspects remain controversial in preclinical and clinical studies [8, 9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
