Open Access

Programmed Death Ligand 1: Unveiling its Impact on Endometrial Carcinogenesis

KOUTRAS ANTONIOS 1
FASOULAKIS ZACHARIAS 1
MOLLAKI VASILIKI 2
PERROS PARASKEVAS 1
THEODOULIDIS VASILIOS 3
SYLLAIOS ATHANASIOS 4
GARMPIS NIKOLAOS 5
  &  
KONTOMANOLIS EMMANUEL N. 6

11st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Athens, Greece

2National Commission for Bioethics and Technoethics, Athens, Greece

31st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, “Papageorgiou” Hospital, Thessaloniki, Greece

41st Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece

5Second Department of Propedeutic Surgery, National and Kapodistrian, University of Athens, Athens, Greece

6Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece

Cancer Diagnosis & Prognosis Mar-Apr; 4(2): 91-96 DOI: 10.21873/cdp.10292
Received 12 November 2023 | Revised 13 April 2024 | Accepted 22 December 2023
Corresponding author
Paraskevas Perros, Resident of Obstetrics and Gynecology, 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece. Tel: +30 6984385055, email: paris_per@yahoo.gr

Abstract

Endometrial cancer is a commonly diagnosed gynecological malignancy presenting an increasing incidence worldwide. The immune response plays a crucial role in the mechanisms underlying carcinogenesis and the progression of tumors. In recent times, there has been a discernible surge in the acknowledgment of the importance of programmed death ligand 1 (PDL1) in evading the immunological response of the host and promoting the growth of malignancies. The primary aim of this review is to consolidate the existing corpus of evidence pertaining to the role of PDL1 in the etiology and progression of endometrial cancer and investigate the molecular mechanisms involved in the expression of PDL1 in cells impacted by endometrial cancer. Finally, the association between PDL1 expression and clinical outcomes, as well as the potential therapeutic uses of targeting the PDL1 pathway are being analyzed.
Keywords: Endometrial cancer, genomic instability, tumor, programmed death ligand 1 (PLD1), tumorigenesis, Oncogenes, review

Endometrial cancer (EC) is the most often diagnosed gynecological malignancy worldwide (1). The global incidence of the disease has been progressively increasing, possibly because of the rising prevalence of obesity, a well-recognized predisposing factor for the ailment (2). The significance of EC is emphasized not only by its widespread prevalence but also by its ability to demonstrate aggressiveness and invasiveness, particularly in later stages (3). The selection of treatment for EC depends on the particular stage and grade of the tumor. Surgical intervention, often including a hysterectomy and bilateral salpingo-oophorectomy, is the main method used in the management of early-stage disease. In later stages of the condition, treatment strategy may include surgical procedures, radiation therapy, chemotherapy, and hormone therapy (4). Hence, there is clearly a need to identify new prognostic markers and therapeutic targets for EC that will facilitate disease management.

The immune system plays a critical role in protecting the host organism against illnesses and also aids in the surveillance of malignancies. Immune checkpoints, such as the programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PDL1), are intricate regulatory mechanisms that modulate immune responses to prevent the development of autoimmunity. Nevertheless, it is plausible that tumors might use these pathways as a mean to evade immune destruction (5). The PD-1 receptor is present on activated T-cells and functions as an inhibitory receptor. In the context of the tumor microenvironment (TME), tumor cells and immune cells produce PDL1, which functions as the ligand for PD-1. The interaction between PDL1 and PD-1 results in the transmission of an inhibitory signal, which impedes the activation and proliferation of T-cells. As a result, this creates a conducive environment for tumor growth by suppressing the immune system (6).

However, the role of PDL1 in endometrial carcinogenesis has not been sufficiently examined. This review aims to provide an informative synthesis of the current state of knowledge on the role of PDL1 in EC and highlight its potential as a prognostic and therapeutic target for EC.

Methodology

A literature review of the Medline (PubMed), Scopus, and Web of Science databases was conducted using the following terms: PDL1 expression, EC, tumor, PD1.

The Etiology of Altered PDL1 Expression in Endometrial Cancer

The etiology of altered PDL1 expression in EC is complex and multifactorial. Up-regulation of PDL1 may be ascribed to genetic and epigenetic modifications, such as DNA methylation and histone modifications (7). Research has also indicated that inflammatory signals within the tumor microenvironment (TME), particularly those facilitated by cytokines, such as interferon-gamma, can increase the expression of PDL1 (8). Furthermore, specific molecular subtypes of EC exhibit a positive correlation with PDL1 expression, which may indicate a genetic predisposition to particular malignancies (9).

Genetic and epigenetic changes in PDL1 expression and cancer. The expression of PDL1 in cancer may be influenced by genetic and epigenetic changes. Genomic variations, such as mutations or copy number variations, may result in the over-expression of PDL1 (10). In a large study investigating the potential of using PDL1 gene copy number (CN) changes as a biomarker for immune checkpoint inhibitor (ICPI) treatment, it was found that PDL1 CN gains were significantly associated with PDL1 positivity and with microsatellite instability (MSI) status in clinically relevant tumor types, including uterine endometrial adenocarcinoma (OR=3.2), which showed low frequencies of PDL1 CN deprivation (16.6%) (n=1,971). Additionally, PDL1 CN gain was significantly correlated with tumor mutational burden (TMB) in only four tumor types including uterine endometrial adenocarcinoma (OR=2.3, p<0.001). In the tumor types in which MSI is most clinically relevant including uterine endometrial adenocarcinoma, a significant correlation was observed between PDL1 CN gains and MSI-High (OR=3.2, p=2.1×10−6). These results demonstrated that the association of PDL1 CN gains with PD-L1 positivity and MSI status, as well as with TMB in uterine endometrial adenocarcinoma can be used as a biomarker for ICPI treatment. Huang et al. analyzed data on PDL1 copy number changes across a large dataset encompassing 244,584 patient samples. As an example, certain signaling pathways associated with the development of cancer, such as the PI3K/AKT/mTOR pathway were shown to be correlated with increased expression of PDL1 (11). The regulation of PDL1 gene is significantly influenced by epigenetic processes whereby DNA methylation patterns and histone modifications are important elements in this regulatory process. Prior studies have shown a positive association between hypomethylation of the promoter region of the PDL1 gene and increased expression in some forms of cancers (12). Furthermore, post-transcriptional regulation, mediated by microRNAs, contributes an extra layer of to the regulation of the expression of PDL1, as shown in chemoresistant ovarian cancer (13).

The influence of the tumor microenvironment. The TME is of utmost importance in the modulation of PDL1 expression in endometrial malignancies. The TME is subject to several influences, one of which is the presence of inflammatory cytokines, particularly interferon-gamma. The aforementioned stimuli induce the expression of PDL1 on both neoplastic cells and immune cells that have invaded the TME (14). Moreover, previous studies have shown that the hypoxic conditions inside the TME might lead to increased PDL1 expression, hence facilitating immune evasion and suppression by the tumor (15). In addition, cancer-associated fibroblasts and tumor cells inside the TME are also involved in the modulation of the PD-1/PDL1 axis (16).

PDL1 Expression as a Potential Prognostic Marker in Endometrial Cancer

The multifaceted role of PDL1 in the progression of EC and its complex interplay with the immune system have garnered growing interest regarding its potential as a prognostic marker. Studies have reported on the association between the expression of PDL1 and the grade of tumors in EC. Increased levels of gene expression are often observed in malignancies characterized by a high degree of cellular differentiation, suggesting a plausible correlation with augmented tumor aggressiveness (17). In addition to tumor grade, associations between PDL1 expression and other prognostic markers, such as lymphovascular invasion and greater depth of myometrial invasion, have been observed (18). Noteworthy, the expression of PDL1 might potentially demonstrate a relationship with certain molecular subtypes of EC, therefore providing significant insights into the intrinsic heterogeneity of this disease (19).

Research has also shown a significant association between increased PDL1 expression levels and reduced rates of both overall survival and disease-free survival (20). Therefore, PDL1 is now becoming recognized as both a potentially effective therapeutic target and a marker for patient classification, enabling the implementation of personalized treatment approaches. The prognostic significance of PDL1 expression, however, may vary depending on the specific context and requires interpretation in conjunction with other clinical and molecular indicators (21-24).

PDL1 Expression and Other Clinicopathological Features

PDL1 expression in EC is not seen in isolation. A significant association exists between the expression of PDL1 and several clinicopathological characteristics. For example, it has been shown that cancers characterized by high microsatellite instability (MSI-H), which is indicative of a failure in mismatch repair, often have increased PDL1 expression levels (25). Furthermore, the complex link between PDL1 and other immunological checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), suggests that PDL1 is involved in the immune evasion mechanisms of the tumor (26). Increased expression of PDL1 has been shown to be related with lymphovascular invasion, deeper myometrial invasion, and higher histological grades, hence introducing additional levels of intricacy in the interpretation of prognosis (27).

In a recent review of the association of PDL1 expression and its association with clinicopathological features in 3023 EC cases, it was found that the overall pooled prevalence of PDL1 expression was 34.26% in tumor cells and 51.39% in immune cells among women with EC. PDL1 expression was found to be significantly associated with Stage III/IV disease (in both tumor and immune cells) and correlated with the presence of lympho-vascular invasion in immune cells. Noteworthy, PDL1 expression in tumor cells was not associated with age, histology types, myometrial invasion, and lympho-vascular invasion, whereas in immune cells, PDL1 expression was not associated with age, histology type, and myometrial invasion. Finally, the meta-analysis revealed a significant correlation with poorer overall survival in patients with high PDL1 expression in immune cells, but not in tumor cells (28,29).

A similar but earlier meta-analysis of 1,615 patients with EC, also showed that high expression of PDL1 was not significantly correlated with overall survival (HR=1.20, 95%CI=0.41-3.52, p=0.737) or progression-free survival (HR=1.12, 95%CI=0.50-2.54, p=0.778), whereas PDL1 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) (30).

The PDL1 Pathway as a Therapeutic Target in Endometrial Cancer

The PD-1/PDL1 pathway is of utmost importance for facilitating the immune system’s capacity to differentiate between self and non-self, hence aiding in the prevention of autoimmunity. In several types of malignancies, such as EC, this biological pathway may be exploited, enabling neoplastic cells to evade immune detection. Given the growing evidence of the involvement of PDL1 in the advancement of EC and the favorable outcomes seen with ICPIs in many malignancies, there is substantial enthusiasm around the potential of targeting the PD-1/PDL1 axis for therapeutic interventions (31,32).

Monoclonal antibodies known as PD-1/PDL1 inhibitors have been specifically developed to impede the interaction between PD-1 and PDL1. There are two main categories: a) PD-1 inhibitors that specifically bind to the PD-1 receptor found on T cells. Prominent examples of PD-1 inhibitors include pembrolizumab (commercially known as Keytruda) and nivolumab (marketed as Opdivo). b) PDL1 inhibitors designed to selectively target PDL1 expressed on tumor cells, as well as other cells present within the TME. Examples of PDL1 inhibitors are atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) (33).

Pembrolizumab, an anti-PD-1 antibody, has shown encouraging outcomes in clinical studies conducted on individuals with EC who had high levels of MSI or mismatch repair deficiency (29). Several studies are currently conducted to evaluate the effectiveness of PD-1/PDL1 inhibitors as standalone treatments and/or in conjunction with other treatments, such as chemotherapy or targeted therapies (31). Furthermore, there is ongoing research to investigate strategies aimed at improving the effectiveness of these inhibitors, including the potential benefits of combining them with radiation therapy or other immunomodulatory drugs (29). As our understanding of the immunological milieu in EC expands, enhanced prospects for efficacious treatment strategies will arise correspondingly.

Numerous clinical studies have been conducted to assess the efficacy of PD-1/PDL1 inhibitors in the context of EC. The clinical study KEYNOTE-028, which included the usage of pembrolizumab, demonstrated positive outcomes in a specific subgroup of individuals with EC. Notably, these good responses were seen in patients with elevated levels of MSI or PDL1 expression (34). A subsequent clinical study using avelumab showed instances of partial responses in individuals with recurrent or persistent EC (35). The studies’ results highlight the potential efficacy of immunotherapy as a treatment for EC, emphasizing the need for patient classification. The findings of different immune checkpoint blockade therapies in gynecological cancers, including EC, have been recently reviewed (36).

Although PD-1/PDL1 inhibitors have shown potential, they are not devoid of obstacles. To begin with, it should be noted that not all patients respond to medication. Additionally, although predictive biomarkers might provide valuable insights, they are not entirely conclusive (37), and there is a noteworthy thought about immune-related adverse effects, which can occur in several organ systems (38). In anticipation of future developments, the use of combination medicines holds significant promise. The augmentation of response rates might potentially be achieved by integrating PD-1/PDL1 inhibitors with other treatment modalities, including chemotherapy, targeted treatments, or other immunotherapies (39). Furthermore, there exists considerable promise in the investigation of alternative immune checkpoints or the development of medicines that directly target the TME.

Recap the Importance of PDL1 in Endometrial Cancer Progression

PDL1 has emerged as a significant factor in the context of EC. The role of PDL1 in facilitating immune evasion by tumor cells contributes to the establishment of a microenvironment that supports the growth of cancer. The association between its expression and advanced-stage disease, recurrence, and lower overall survival has been demonstrated (22,23). The use of the PD-1/PDL1 axis as a mechanism for immune evasion highlights the potential advantages of targeting therapeutic interventions to this pathway. The association between PDL1 and other clinical-pathological characteristics, such as MSI and higher histological grades, underscores its pivotal involvement in the progression of EC (25,27).

Currently, precision medicine aims to customize medical therapies based on specific patient characteristics, with the goal of maximizing therapeutic efficacy and decreasing the occurrence of side effects. Biomarkers, such as the expression of PDL1 or the status of MSI, have the potential to inform therapy choices, therefore identifying individuals who are most likely to get significant benefits from PD-1/PDL1 inhibitors (34). The process of patient stratification has the potential to provide improved results, particularly when used in conjunction with other molecular and genetic indicators. With the advancement of multi-omics technologies, there is an expectation of adopting a comprehensive and patient-centered strategy that integrates genomics, transcriptomics, and immune profiling to develop optimal treatment methods (40).

Conclusion

Significant progress has been achieved in comprehending the involvement of PDL1 in EC; yet, there exist various domains that need further investigation. One of the primary obstacles is the understanding of the processes of resistance. Despite the potential efficacy of PD-1/PDL1 inhibitors, the development of resistance, whether it is inherent or acquired, continues to pose a substantial challenge. Understanding the processes behind this resistance is essential for optimizing treatment approaches (41). Combination of medicines provide a potentially fruitful approach. As previously shown, there exists promise in the integration of PD-1/PDL1 inhibitors with complementary therapeutic approaches. The identification of the most effective combinations, sequences, and dosage regimens will be a crucial undertaking in the future (35). Moreover, in addition to the realm of PDL1, there is a need to delve into the wider TME and its many immunological complexities. Gaining a more profound comprehension in this context will provide valuable insights into other treatment targets (42). In conclusion, the current use of PDL1 expression and MSI status as biomarkers represents a continuous effort to identify more accurate and comprehensive predictors of response to immunotherapy (43).

Conflicts of Interest

The Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

A.K., Z.F., and V.M. contributed to conception and design. E.N.K. was responsible for overall supervision. P.P., A.S.; Drafted the manuscript, which was revised by N.G. and V.T.. All Authors read and approved the final manuscript.

Acknowledgements

The Authors are grateful to all who provided assistance during the preparation of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D & Bray F Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136(5) E359 - 86 2015. DOI: 10.1002/ijc.29210
2 Renehan AG Tyson M Egger M Heller RF & Zwahlen M Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 371(9612) 569 - 578 2008. DOI: 10.1016/S0140-6736(08)60269-X
3 Bokhman JV Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15(1) 10 - 17 1983. DOI: 10.1016/0090-8258(83)90111-7
4 Morice P Leary A Creutzberg C Abu-Rustum N & Darai E Endometrial cancer. Lancet. 387(10023) 1094 - 1108 2016. DOI: 10.1016/S0140-6736(15)00130-0
5 Pardoll DM The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12(4) 252 - 264 2012. DOI: 10.1038/nrc3239
6 Dong H Strome SE Salomao DR Tamura H Hirano F Flies DB Roche PC Lu J Zhu G Tamada K Lennon VA Celis E & Chen L Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 8(8) 793 - 800 2002. DOI: 10.1038/nm730
7 Barsoum IB Smallwood CA Siemens DR & Graham CH A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74(3) 665 - 674 2014. DOI: 10.1158/0008-5472.CAN-13-0992
8 Garcia-Diaz A Shin DS Moreno BH Saco J Escuin-Ordinas H Rodriguez GA Zaretsky JM Sun L Hugo W Wang X Parisi G Saus CP Torrejon DY Graeber TG Comin-Anduix B Hu-Lieskovan S Damoiseaux R Lo RS & Ribas A Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19(6) 1189 - 1201 2017. DOI: 10.1016/j.celrep.2017.04.031
9 Cancer Genome Atlas Research Network Kandoth C Schultz N Cherniack AD Akbani R Liu Y Shen H Robertson AG Pashtan I Shen R Benz CC Yau C Laird PW Ding L Zhang W Mills GB Kucherlapati R Mardis ER & Levine DA Integrated genomic characterization of endometrial carcinoma. Nature. 497(7447) 67 - 73 2013. DOI: 10.1038/nature12113
10 Chen L Gibbons DL Goswami S Cortez MA Ahn YH Byers LA Zhang X Yi X Dwyer D Lin W Diao L Wang J Roybal J Patel M Ungewiss C Peng D Antonia S Mediavilla-Varela M Robertson G Suraokar M Welsh JW Erez B Wistuba II Chen L Peng D Wang S Ullrich SE Heymach JV Kurie JM & Qin FX Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 5 5241 2014. DOI: 10.1038/ncomms6241
11 Peng W Liu C Xu C Lou Y Chen J Yang Y Yagita H Overwijk WW Lizée G Radvanyi L & Hwu P PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72(20) 5209 - 5218 2012. DOI: 10.1158/0008-5472.CAN-12-1187
12 Goltz D Gevensleben H Dietrich J & Dietrich D PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients. Oncoimmunology. 6(1) e1257454 2016. DOI: 10.1080/2162402X.2016.1257454
13 Xu S Tao Z Hai B Liang H Shi Y Wang T Song W Chen Y OuYang J Chen J Kong F Dong Y Jiang SW Li W Wang P Yuan Z Wan X Wang C Li W Zhang X & Chen K miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun. 7 11406 2016. DOI: 10.1038/ncomms11406
14 Taube JM Klein A Brahmer JR Xu H Pan X Kim JH Chen L Pardoll DM Topalian SL & Anders RA Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 20(19) 5064 - 5074 2014. DOI: 10.1158/1078-0432.CCR-13-3271
15 Noman MZ Desantis G Janji B Hasmim M Karray S Dessen P Bronte V & Chouaib S PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 211(5) 781 - 790 2014. DOI: 10.1084/jem.20131916
16 Asif PJ Longobardi C Hahne M & Medema JP The role of cancer-associated fibroblasts in cancer invasion and metastasis. Cancers (Basel). 13(18) 4720 2021. DOI: 10.3390/cancers13184720
17 Vanderstraeten A Luyten C Verbist G Tuyaerts S & Amant F Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy. Cancer Immunol Immunother. 63(6) 545 - 557 2014. DOI: 10.1007/s00262-014-1537-8
18 Peng W Liu C Xu C Lou Y Chen J Yang Y Yagita H Overwijk WW Lizée G Radvanyi L & Hwu P PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72(20) 5209 - 5218 2012. DOI: 10.1158/0008-5472.CAN-12-1187
19 Cancer Genome Atlas Research Network Albert Einstein College of Medicine Analytical Biological Services Barretos Cancer Hospital Baylor College of Medicine Beckman Research Institute of City of Hope Buck Institute for Research on Aging Canada’s Michael Smith Genome Sciences Centre Harvard Medical School Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services HudsonAlpha Institute for Biotechnology ILSbio,LLC Indiana University School of Medicine Institute of Human Virology Institute for Systems Biology International Genomics Consortium Leidos Biomedical Massachusetts General Hospital McDonnell Genome Institute at Washington University Medical College of Wisconsin Medical University of South Carolina Memorial Sloan Kettering Cancer Center Montefiore Medical Center NantOmics National Cancer Institute National Hospital, Abuja, Nigeria National Human Genome Research Institute National Institute of Environmental Health Sciences National Institute on Deafness &Other Communication Disorders Ontario Tumour Bank, London Health Sciences Centre Ontario Tumour Bank, Ontario Institute for Cancer Research Ontario Tumour Bank, The Ottawa Hospital Oregon Health &Science University Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center SRA International St Joseph’s Candler Health System Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University Research Institute at Nationwide Children’s Hospital Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University University of Bergen University of Texas MD Anderson Cancer Center University of Abuja Teaching Hospital University of Alabama at Birmingham University of California, Irvine University of California Santa Cruz University of Kansas Medical Center University of Lausanne University of New Mexico Health Sciences Center University of North Carolina at Chapel Hill University of Oklahoma Health Sciences Center University of Pittsburgh University of São Paulo Ribeir ão Preto Medical School University of Southern California University of Washington University of Wisconsin School of Medicine &Public Health Van Andel Research Institute & Washington University in St Louis Integrated genomic and molecular characterization of cervical cancer. Nature. 543(7645) 378 - 384 2017. DOI: 10.1038/nature21386
20 Howitt BE Sun HH Roemer MG Kelley A Chapuy B Aviki E Pak C Connelly C Gjini E Shi Y Lee L Viswanathan A Horowitz N Neuberg D Crum CP Lindeman NL Kuo F Ligon AH Freeman GJ Hodi FS Shipp MA & Rodig SJ Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol. 2(4) 518 2016. DOI: 10.1001/jamaoncol.2015.6326
21 Santin AD Bellone S Buza N Choi J Schwartz PE Schlessinger J & Lifton RP Regression of chemotherapy-resistant polymerase ε (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res. 22(23) 5682 - 5687 2016. DOI: 10.1158/1078-0432.CCR-16-1031
22 Howitt BE Shukla SA Sholl LM Ritterhouse LL Watkins JC Rodig S Stover E Strickland KC D’Andrea AD Wu CJ Matulonis UA & Konstantinopoulos PA Association of polymerase e–mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 1(9) 1319 2015. DOI: 10.1001/jamaoncol.2015.2151
23 Mezache L Paniccia B Nyinawabera A & Nuovo GJ Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod Pathol. 28(12) 1594 - 1602 2015. DOI: 10.1038/modpathol.2015.108
24 Engerud H Berg HF Myrvold M Halle MK Bjorge L Haldorsen IS Hoivik EA Trovik J & Krakstad C High degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer. Gynecol Oncol. 157(1) 260 - 267 2020. DOI: 10.1016/j.ygyno.2020.01.020
25 Dudley JC Lin MT Le DT & Eshleman JR Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 22(4) 813 - 820 2016. DOI: 10.1158/1078-0432.CCR-15-1678
26 Zou W Wolchok JD & Chen L PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 8(328) 328rv4 2016. DOI: 10.1126/scitranslmed.aad7118
27 O’Malley DM Matulonis UA Birrer MJ Castro CM Gilbert L Vergote I Martin LP Mantia-Smaldone GM Martin AG Bratos R Penson RT Malek K & Moore KN Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 157(2) 379 - 385 2020. DOI: 10.1016/j.ygyno.2020.01.037
28 Mamat Yusof MN Chew KT Kampan N Abd Aziz NH Md Zin RR Tan GC & Shafiee MN PD-L1 expression in endometrial cancer and its association with clinicopathological features: a systematic review and meta-analysis. Cancers (Basel). 14(16) 3911 2022. DOI: 10.3390/cancers14163911
29 Le DT Uram JN Wang H Bartlett BR Kemberling H Eyring AD Skora AD Luber BS Azad NS Laheru D Biedrzycki B Donehower RC Zaheer A Fisher GA Crocenzi TS Lee JJ Duffy SM Goldberg RM de la Chapelle A Koshiji M Bhaijee F Huebner T Hruban RH Wood LD Cuka N Pardoll DM Papadopoulos N Kinzler KW Zhou S Cornish TC Taube JM Anders RA Eshleman JR Vogelstein B & Diaz LA Jr PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372(26) 2509 - 2520 2015. DOI: 10.1056/NEJMoa1500596
30 Lu L Li Y Luo R Xu J Feng J & Wang M Prognostic and clinicopathological role of PD-L1 in endometrial cancer: a meta-analysis. Front Oncol. 10 632 2020. DOI: 10.3389/fonc.2020.00632
31 Ott PA Bang YJ Piha-Paul SA Razak ARA Bennouna J Soria JC Rugo HS Cohen RB O’Neil BH Mehnert JM Lopez J Doi T van Brummelen EMJ Cristescu R Yang P Emancipator K Stein K Ayers M Joe AK & Lunceford JK T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 37(4) 318 - 327 2019. DOI: 10.1200/JCO.2018.78.2276
32 Sharabi AB Lim M Deweese TL & Drake CG Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16(13) e498 - e509 2015. DOI: 10.1016/S1470-2045(15)00007-8
33 Zou W & Chen L Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immuno. 8(6) 467 - 477 2008. DOI: 10.1038/nri2326
34 Ott PA Piha-Paul SA Munster P Pishvaian MJ van Brummelen EMJ Cohen RB Gomez-Roca C Ejadi S Stein M Chan E Simonelli M Morosky A Saraf S Emancipator K Koshiji M & Bennouna J Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 28(5) 1036 - 1041 2017. DOI: 10.1093/annonc/mdx029
35 Disis ML Taylor MH Kelly K Beck JT Gordon M Moore KM Patel MR Chaves J Park H Mita AC Hamilton EP Annunziata CM Grote HJ von Heydebreck A Grewal J Chand V & Gulley JL Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: Phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. 5(3) 393 - 401 2019. DOI: 10.1001/jamaoncol.2018.6258
36 Peng H He X & Wang Q Immune checkpoint blockades in gynecological cancers: A review of clinical trials. Acta Obstet Gynecol Scand. 101(9) 941 - 951 2022. DOI: 10.1111/aogs.14412
37 Tumeh PC Harview CL Yearley JH Shintaku IP Taylor EJ Robert L Chmielowski B Spasic M Henry G Ciobanu V West AN Carmona M Kivork C Seja E Cherry G Gutierrez AJ Grogan TR Mateus C Tomasic G Glaspy JA Emerson RO Robins H Pierce RH Elashoff DA Robert C & Ribas A PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515(7528) 568 - 571 2014. DOI: 10.1038/nature13954
38 Postow MA Sidlow R & Hellmann MD Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 378(2) 158 - 168 2018. DOI: 10.1056/NEJMra1703481
39 Ribas A & Wolchok JD Cancer immunotherapy using checkpoint blockade. Science. 359(6382) 1350 - 1355 2018. DOI: 10.1126/science.aar4060
40 Haslem DS Chakravarty I Fulde G Gilbert H Tudor BP Lin K Ford JM & Nadauld LD Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs. Oncotarget. 9(15) 12316 - 12322 2018. DOI: 10.18632/oncotarget.24384
41 Sharma P Hu-Lieskovan S Wargo JA & Ribas A Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 168(4) 707 - 723 2017. DOI: 10.1016/j.cell.2017.01.017
42 Binnewies M Roberts EW Kersten K Chan V Fearon DF Merad M Coussens LM Gabrilovich DI Ostrand-Rosenberg S Hedrick CC Vonderheide RH Pittet MJ Jain RK Zou W Howcroft TK Woodhouse EC Weinberg RA & Krummel MF Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 24(5) 541 - 550 2018. DOI: 10.1038/s41591-018-0014-x
43 Goodman AM Kato S Bazhenova L Patel SP Frampton GM Miller V Stephens PJ Daniels GA & Kurzrock R Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 16(11) 2598 - 2608 2017. DOI: 10.1158/1535-7163.MCT-17-0386