A snapshot of the PD-1/PD-L1 pathway

Abstract

Cancer cells can evade the attack from host immune systems via hijacking the regulatory circuits mediated by immune checkpoints. Therefore, reactivating the antitumor immunity by blockade of immune checkpoints is considered as a promising strategy to treat cancer. Programmed death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) are critical immune checkpoint proteins that responsible for negative regulation of the stability and the integrity of T-cell immune function. Anti-PD-1/PD-L1 drugs have been developed for immune checkpoint blockade and can induce clinical responses across different types of cancers, which provides a new hope to cure cancer. However, the patients' response rates to current anti-PD-1 or anti-PD-L1 therapies are still low and many initial responders finally develop resistance to these therapies. In this review, we provides a snapshot of the PD-1/PD-L1 molecular structure, mechanisms controlling their expression, signaling modulated by PD-1/PD-L1, current anti-PD-1/PD-L1 therapies, and the future perspectives to overcome the resistance.

Keywords: PD-1; PD-L1; PD-L2; T cell; cancer immunotherapy; immune checkpoint.

Figure 1

The pathway of programmed cell death (PD) and Cytotoxic T lymphocyte antigen-4 (CTLA-4) in suppression of T-cell activation. The MHC-TCR interaction together with B7-1/2-CD28 interaction stimulate T-cell activation. On the contrary, CTLA-4 binds to B7-1/2 and mediates inhibitory signal to prevent T-cell activation. There are at least five interacting molecules in the PD pathway: PD-1, PD-L1, PD-L2, B7-1 (CD80), and RGM-2. PD-L1 and PD-L2 are ligands of PD-1, and the PD-L1/PD-L2 binding with PD-1 leads to suppression of T-cell activation. PD-L1 also interacts with B7-1 (CD80) on activated T-cells to inhibit T-cell activity. PD-L2 has its second receptor RGM-2. The PD-L2-RGM-2 interaction mediates respiratory tolerance.

Figure 2

Adaptive resistance to tumor immunity mediated by PD-1/PD-L1. Following activation in lymphoid organs, tumor-specific Teffs enter the tumor site to develop TILs. Upon recognition of tumor antigens, TILs release cytokines such as IFN-γ, which stimulates the expression of PD-L1 in the tumor microenvironment. By binding to PD-1, PD-L1 provides a suppressive signal to T-cells and an anti-apoptotic signal to tumor cells, leading to T-cell dysfunction and tumor survival.