Programmed Death Ligand-1 (PD-L1) Expression in the Programmed Death Receptor-1 (PD-1)/PD-L1 Blockade: A Key Player Against Various Cancers

Abstract

Context.— Immune checkpoint pathways, including programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) signaling pathway, which are important in mediating self-tolerance and controlling self-damage, can sometimes be manipulated by cancer cells to evade immune surveillance. Recent clinical trials further demonstrate the efficacy of PD-1/PD-L1–targeted therapy in various cancers and reveal a new era of cancer immunotherapy. Objective.— To review the mechanism of the PD-1/PD-L1 signaling pathway, the regulation of this pathway, PD-1/PD-L1 as a predictive and/or prognostic marker in various cancers, and strategies of measuring PD-L1 expression. Data Sources.— Representative medical literature regarding PD-L1 expression in various cancers, including the preliminary results of the Blue Proposal, which compares different immunohistochemical stains for PD-L1 reported in the recent American Association of Cancer Research (AACR) Annual Meeting (April 16–20, 2016). Conclusion.— Either PD-1/PD-L1–targeted therapy alone or in combination with other treatment modalities provides benefit for patients with advanced cancers. Because of the complexity of cancer immunity, we still do not have a reliable biomarker to predict the response of PD-1/PD-L1–targeted therapy. Future studies, including methods beyond immunohistochemical stains, are needed to develop reliable biomarker/biomarkers for pathology laboratories to aid in selecting patients who will benefit most from PD-1/PD-L1–targeted therapy.

Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer

“…In addition, PD-L1 antibodies used in IHC staining differ among various studies and different cut-off values of PD-L1 positivity are used, making it difficult to compare results across studies. Indeed, different companion antibodies of PD-L1 made by various pharmaceutical manufacturers have been used in clinical trials (25). Although PD-L1 expression was evaluated by IHC staining of SCLC cells in the present study, it has not been established whether PD-L1 expression is correlated with clinical response and outcome.…”

Biomarkers for immune checkpoint inhibitors: The importance of tumor topography and the challenges to cytopathology

“…Unlike targeted therapies, which are often designed for small subgroups of a tumor type containing uncommon genetic mutations (eg, vemurafenib for BRAF‐mutant melanoma), immunotherapies often have efficacy across multiple tumor types and are not restricted to uncommon subsets. Also, unlike targeted therapies, to which drug resistance almost invariably emerges after weeks or months, responses to immunotherapies may last for years …”

Novel regulators of PD-L1 expression in cancer: CMTM6 and CMTM4—a new avenue to enhance the therapeutic benefits of immune checkpoint inhibitors

“…However, this approach has been constantly challenged by the complexity and diversity of gene mutations and protein modification present in human cancers as well a complex tumor microenvironment, resulting in limited or failed therapeutic success (1)(2)(3). Recently discovered immune checkpoint pathways, including programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) signaling pathway, were shown to protect host from overactive T-effector cells not only in cancer but also during microbial infections (4,5).…”

“…PD-1 is preferentially expressed on activated T-cells with particularly high expression in the population of tumor-infiltrating T-cells, while PD-L1, one of its key ligands, has been found to be overexpressed (activated) in various solid malignancies, most notably in malignant melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma, advanced urothelial carcinoma and various solid cancers exhibiting high mutational load and/or microsatellite instability (MSI-H) (2,6,7). PD-L1 activation has also been described in hematologic malignancies, such as multiple myeloma, both non-Hodgkin and Hodgkin lymphomas (most notable in classical Hodgkin lymphoma), some leukemias as well as systemic histiocytoses (3,(8)(9)(10).…”

“…However, cancer cells frequently manipulate PD-1/PD-L1 axis to evade immune surveillance (3,12). Therefore, only a subset of patients respond to these agents and fewer still achieve a durable response (11).…”