LAUSR

Immunotherapy has revolutionized cancer care, with immune checkpoint inhibitors targeting the PD-1/PDL1 axis leading to impressive responses in a variety of malignancies, including gynecologic cancers (1,2). Immune checkpoints normally modulate the amplitude and duration of immune response in a healthy immune system, and may be either immune-activating or immunosuppressive. They are typically expressed on inflammatory cells—most often T cells—and function via interactions with ligands expressed on the surface of antigen-presenting cells. However, this mechanism may be co-opted by malignancies, which can express immunosuppressive checkpoint ligands as a mechanism of immune evasion (3–5). Checkpoint inhibitor-based immunotherapy blocks this immunosuppressive interaction by targeting either the checkpoint (such as PD-1), or its ligand (such as PD-L1). With the PD-1/PD-L1 axis no longer intact, the patient’s adaptive immune system is able to target the tumor via cytotoxic T-cell–mediated attack. In 2018, one such checkpoint inhibitor—the antiPD-1 drug pembrolizumab—was approved by the Food & Drug Administration (FDA) for the treatment of advanced cervical cancer demonstrating a PD-L1 combined positive score (CPS) of at least 1 by immunohistochemistry (22C3 pharmDX kit, Agilent) (6). This approval was based on results from the Phase II KEYNOTE-158 study, which showed response to therapy in a subset of PD-L1-positive cervical squamous cell carcinomas and adenocarcinomas. The study included a total of 98 advanced cervical cancer patients (92 squamous cell carcinomas, 5 adenocarcinomas, and 1 adenosquamous carcinoma), 77 of whom had received prior chemotherapy. The vast majority—84%—had a PD-L1 CPS≥ 1 (7). Twelve patients, including 1 adenocarcinoma, showed some response to therapy, and all responders were PD-L1 positive. Complete response was seen in just under 4% of patients (including <3% of previously treated cases), while 11% overall showed partial response and 18% had stable disease. Because all complete and partial responses were restricted to the PD-L1 CPS-positive group, expression became a criterion for treatment eligibility in the FDA recommendation that emerged from this study. Although there is no comparable FDA approval in vulvar carcinomas, early evidence suggests that PD-L1 expression may also be a useful predictive biomarker in these tumors (8). Given that the PD-L1 CPS is required to determine anti-PD-1 checkpoint inhibitor candidacy in advanced cervical cancer patients, gynecologic pathologists should to be familiar this scoring system. The CPS was initially designed for upper gastrointestinal carcinomas, where utilization of the tumor proportion score —which accounts for PD-L1 expression exclusively on tumor cells—failed to capture all pembrolizumab responders (9). The CPS accounts not only for PD-L1 tumor cell expression, but also for staining on tumorassociated lymphocytes and macrophages (9–11). It is calculated based on the following equation: [(total number of PD-L1-positive tumor cells, lymphocytes, and macrophages)/(total number of viable tumor cells)]×100. Any CPS from 1 to 100 is considered positive, and 100 is the maximum allowable score. From the Department of Pathology, University of Virginia, Charlottesville, Virginia. The author declares no conflict of interest. Address correspondence to Anne M. Mills, MD, Department of Pathology, University of Virginia, Charlottesville 22908, Virginia. Email: [email protected].