The Controversial Role of PD-1 and Its Ligands in Gynecological Malignancies

Marinelli, Oliviero; Annibali, Daniela; Aguzzi, Cristina; Tuyaerts, Sandra; Amant, Frédéric; Morelli, Maria Beatrice; Santoni, Giorgio; Amantini, Consuelo; Maggi, Federica; Nabissi, Massimo

doi:10.3389/fonc.2019.01073

Cited by 35 publications

(40 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, blocking antibodies against PD-1 (such as Nivolumab and Pembrolizumab) and against PD-L1 (such as Atezolizumab) have been approved by the US Food and Drug Administration (FDA) for melanoma, nonsmall-cell lung cancers and MSI tumors (8). Regarding PD-L2, less is known about its role in cancer, and up to now, there is little information available in EC, especially for nonendometrioid EC (9). 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).…”

Section: Discussionmentioning

confidence: 99%

“…The most promising immunotherapeutic approach involves antibodies targeting the immune checkpoint inhibitor (ICI) molecules, as demonstrated in Hodgkin's lymphoma in which programmed death 1 (PD-1, CD279) receptor blockage resulted in response rate of 87%, probably based on the molecular upregulation of PD-1 and its ligands (PD-Ls) pathways (6,7). 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). PD-L1 (B7-H1, CD274) and PD-L2 (PDCD1LG2, B7-DC, CD273) are immune co-signaling molecules belonging to the B7 family, and they are expressed in several cancer types (6,10) and, also, in infiltrating immune cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…PD-L1 (B7-H1, CD274) and PD-L2 (PDCD1LG2, B7-DC, CD273) are immune co-signaling molecules belonging to the B7 family, and they are expressed in several cancer types (6,10) and, also, in infiltrating immune cells (11,12). However, the prognostic value of PD-1 ligands is still debated, and their role, when expressed in the tumor microenvironment, has not been fully elucidated yet (9). It is known that PD-L1 and PD-L2 interaction with PD-1 receptor contributes to the strong inhibition of T-cell antitumor effects, resulting in immune escape (10,13,14).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In recent years, we can encourage them to actively access potential treatment opportunities, such as participating in clinical trials of cutting-edge drugs [36]. In the GOG240 trial, compared with the chemotherapy group alone, chemotherapy combined with bevacizumab group continued to show signi cant improvement in OS in persistent, recurrent, or metastatic patients [37].…”

Section: Discussionmentioning

confidence: 99%

Nomogram for predicting the overall survival of cervical cancer patients with nonsurgical treatment

Song

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Surgery is an important treatment for cervical cancer, but some patients choose not to operate on the primary site. The purpose of this study was to establish nomogram for predicting overall survival (OS) in nonsurgical cervical cancer on the primary site(NSCC) patients by using cases in the public database.Methods: All patients diagnosed between 2004 and 2015 were randomly divided into training (n=4283) or validation (n=1832) cohort. Cox regression analysis was used on the training cohort to select independent prognostic factors to construct nomogram for predicting 3- and 5-year OS. In two cohorts, receiver operating characteristic curve (ROC), Harrell’s concordance index (C-index), calibration curves and decision curve analysis (DCA) were used to evaluate the accuracy and the reliability of the model. We made a risk stratification system based on the model and performed Kaplan-Meier survival analysis on the risk level.Results: In the training set, ten clinicopathological factors were significantly correlated with survival outcomes and were included in the nomogram. In the training cohort and validation cohort, the C-index, ROC and calibration plots exhibited an excellent consistency between actual OS and model predictions. DCA indicated great clinical benefit. Compared with FIGO staging, nomogram's evaluation effect is superior.Conclusions: Age, histological type, grade, tumor size, extension, lymph node involvement, distant metastasis, lymph node removed, chemotherapy and radiotherapy were independent prognostic factors for OS in NSCC patients. The model showed more satisfactory accuracy and clinical practicability than FIGO staging system, and may provide integration and improvement for therapeutic decisions.

show abstract

“…To date, immunotherapy with checkpoint inhibitors has been demonstrated to have the ability to improve gynecologic cancer clinical trial outcomes [14]. For instance, the positive modulation of adaptive immunity through anti-PD-1 or anti-PD-L1 antibodies promotes T cell proliferation, enhances the anti-tumor effect of T cells and represses the immune escape of cancer cells, ultimately resulting in gynecological tumor regression [15]. Most previous researches have concentrated on the function of proteins in this progression, but further research on the speci c functions of RNAs is still relatively scant [16].…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of immune-related genes in endometrial carcinoma

Wang

Liu

Guan

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Exploring novel and sensitive targets is urgent due to the high morbidity of endometrial cancer (EC). The purpose of our study was to explore the transcription factors and immune-related genes in EC and further identify immune-based lncRNA signature as biomarker for predicting survival prognosis.Methods: Transcription factors, aberrantly expressed immune-related genes and immune-related lncRNAs were explored through bioinformatics analysis. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were conducted to identify the immune and overall survival (OS) related lncRNAs. The accuracy of model was evaluated by Kaplan-Meier method and receiver operating characteristic (ROC) analysis, and the independent prognostic indicator was identified with Cox analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to detect the accuracy of our results.Results: A network of 29 transcription factors and 17 immune-related genes was constructed. Furthermore, four immune-prognosis-related lncRNAs were screened out. Kaplan-Meier survival analysis and time-dependent ROC analysis revealed a satisfactory predictive potential of the 4-lncRNA model. Consistency was achieved among the results from the training set, testing set and entire cohort. The distributed patterns between the high- and low-risk groups could be distinguished in principal component analysis. Comparisons of the risk score and clinical factors confirmed the four-lncRNA-based signature as an independent prognostic indicator. Last, the reliability of the results was verified by qRT-PCR in 29 cases of endometrial carcinoma and in cells.Conclusions: Overall, our study constructed a network of transcription factors and immune-related genes and explored a four immune-related lncRNA signature that could serve as a novel potential biomarker of EC.

show abstract

The Controversial Role of PD-1 and Its Ligands in Gynecological Malignancies

Cited by 35 publications

References 73 publications

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

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

Nomogram for predicting the overall survival of cervical cancer patients with nonsurgical treatment

Integrated analysis of immune-related genes in endometrial carcinoma

Contact Info

Product

Resources

About