PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations

Abstract

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future.

Keywords: PD-1; PD-L1; checkpoint; immunotherapy; tumor.

Figure 1.

PD-1 and PD-L1 interactions affect TIL function in the tumor microenvironment. In the tumor microenvironment, PD-L1 which can bind to PD-1, is abnormally highly expressed on tumor cells and APCs. Activation of PD-1/PD-L1 signaling can cause phosphorylation of tyrosine residues in the PD-1 cytoplasmic ITIM and ITSM structure domains, decreasing the antitumor activity of TILs by inducing apoptosis, inhibiting granular enzyme and perforin production, decreasing IFN-γ, IL-2, and TNF-α secretion, and stagnating the cell cycle. TCR: T cell receptor; MHC: major histocompatibility complex; APC: antigen presenting cell; ITIM: immune receptor tyrosine-based inhibitory motif; ITSM: immune receptor tyrosine-based switch motif; TIL: tumor-infiltrating lymphocytes. →:activation effect;“┤”inhibitory effect.

Figure 2.

Combination therapies with anti-PD-1/PD-L1 antibodies. Because of the complexity of the tumor microenvironment and the complexity of checkpoint regulation in TILs, only partially successful clinical results of PD-1/PD-L1 blockade have been achieved in certain tumors. Therefore, combination therapies are required. Ongoing studies, such as using PD-1/PD-L1 antibodies combined with other checkpoint antibodies, tumor vaccines, antiviral drugs, anti-microbiome modulation, chemotherapy and radiation therapies, or kinase or enzyme inhibitors are being developed. Combination therapies will be a future direction for cancer patient treatment.