Abstract
Programmed cell death-1 and programmed cell death ligand-1 (PD-1/PD-L1) blockage has become an important treatment modality after approval of pembrolizumab and nivolumab by Food and Drug Administration in advanced cancers. Patients with metastatic and recurrent cervical cancer have limited treatment options and usually receive palliative platinum-based chemotherapy without significant survival benefit. Recent studies provided support for usage of immune checkpoint inhibitors in advanced cervical cancer. Around 35% of cervical squamous cell carcinoma (C-SCC) and 17% of adenocarcinomas expressed PD-L1. Human Papilloma Virus status was also correlated with PD-L1 expression. PD-1/PD-L1 expression in tumor infiltrating inflammatory cells was higher in cervical cancer in comparison to endometrial and ovarian adenocarcinomas. In C-SCC diffuse PD-L1 expression as compared to marginal PD-L1 expression on the interface between tumor and stroma was a risk factor for poor disease-free and disease-specific survival rates. Higher numbers of infiltrating regulatory T cells in PD-L1 positive tumors was associated with better prognosis. The studies performed on other cancer types revealed PD-L1 tumor heterogeneity and transient marker expression. Drug-resistance to immune checkpoint inhibitors is also a potential problem. Currently Phase I/II clinical trials evaluating effects of PD-1 therapy are in progress for cervical carcinoma. Additional studies are required to develop novel biomarkers and for standard evaluation of PD-L1 testing in order to predict response to immune checkpoint inhibitors in all cancer types including cervical carcinoma.
Highlights
Cervical cancer is the third common gynecologic cancer and will affect 13,240 women in the United Stated with an estimated 4,170 deaths in 2018 [1]
Human Papilloma Virus (HPV) infection is an etiologic agent of precursor lesions, Cervical Intraepithelial Neoplasia (CIN), and invasive cervical carcinoma [2]
For early staged cancer surgical removal through radical hysterectomy is the treatment of choice and concurrent chemoradiation (CCRT) is the standard treatment modality for locally advanced disease defined as stages IB2-IVA by International Federation of Gynecology and Obstetrics [5]
Summary
Cervical cancer is the third common gynecologic cancer and will affect 13,240 women in the United Stated with an estimated 4,170 deaths in 2018 [1]. Epithelial growth factor inhibitors, targeting of PI3K/AKT/mTOR pathway and therapeutic vaccines are other new treatment modalities included in clinical trials of recurrent and metastatic diseases [12,13,14]. We will discuss below Programmed cell death-1 and programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway and the potential role of PD-1/PD-L1 blockers in the treatment of cervical carcinoma. Several cancer types overexpress PD-L1, which serves as an immune resistance mechanism by inactivating T cells within tumor microenvironment [19,20].
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