Regulatory mechanisms of PD-1/PD-L1 in cancers

Abstract

Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.

Case report: A rare case of anti-PD-1 sintilimab-induced agranulocytosis/severe neutropenia in non-small cell lung cancer and literature review

“…In recent years, significant advancements have been made in cancer immunotherapy, particularly with the advent of widely used immune checkpoint inhibitors (ICIs), such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, which can prolong patient survival ( 1 ). PD-1 and PD-L1 are inhibitory co-stimulatory molecules that serve as negative immune regulatory factors, playing a pivotal role in adaptive cellular immunity.…”

“…PD-1 and PD-L1 are inhibitory co-stimulatory molecules that serve as negative immune regulatory factors, playing a pivotal role in adaptive cellular immunity. By selectively binding to the receptor molecule PD-1 on T cells, tumor-expressed PD-L1 is involved in modulating T cell activation and differentiation while also impeding the anti-tumor immune response mediated by T cells ( 1 ). Blocking the PD-1/PD-L1 signaling pathway with drugs or monoclonal antibodies has emerged as a novel cancer immunotherapy strategy, demonstrating efficacy in treating various types of cancers, including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma and gastric cancer ( 1 , 2 ).…”

“…By selectively binding to the receptor molecule PD-1 on T cells, tumor-expressed PD-L1 is involved in modulating T cell activation and differentiation while also impeding the anti-tumor immune response mediated by T cells ( 1 ). Blocking the PD-1/PD-L1 signaling pathway with drugs or monoclonal antibodies has emerged as a novel cancer immunotherapy strategy, demonstrating efficacy in treating various types of cancers, including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma and gastric cancer ( 1 , 2 ). Despite the effectiveness of these therapies, the potential for immune-related adverse events (irAEs) cannot be ignored.…”