Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond

Immunotherapies that target PD-1/PD-L1 axis have shown unprecedented success in a wide variety of human cancers. PD-1 is one of the key coinhibitory receptors expressed on T cells upon T cell activation. After engagement with its ligands, mainly PD-L1, PD-1 is activated and recruits the phosphatase SHP-2 in proximity to T cell receptor (TCR) and CD28 signaling. This event results in dephosphorylation and attenuation of key molecules in TCR and CD28 pathway, leading to inhibition of T cell proliferation, activation, cytokine production, altered metabolism and cytotoxic T lymphocytes (CTLs) killer functions, and eventual death of activated T cells. Bodies evolve coinhibitory pathways controlling T cell response magnitude and duration to limit tissue damage and maintain self-tolerance. However, tumor cells hijack these inhibitory pathways to escape host immune surveillance by overexpression of PD-L1. This provides the scientific rationale for clinical application of immune checkpoint inhibitors in oncology. The aberrantly high expression of PD-L1 in tumor microenvironment (TME) can be attributable to the “primary” activation of multiple oncogenic signaling and the “secondary” induction by inflammatory factors such as IFN-γ. Clinically, antibodies targeting PD-1/PD-L1 reinvigorate the “exhausted” T cells in TME and show remarkable objective response and durable remission with acceptable toxicity profile in large numbers of tumors such as melanoma, lymphoma, and mismatch-repair deficient tumors. Nevertheless, most patients are still refractory to anti-PD-1/PD-L1 therapy. Identifying the predictive biomarkers and design rational PD-1-based combination therapy become the priorities in cancer immunotherapy. PD-L1 expression, cytotoxic T lymphocytes infiltration, and tumor mutation burden (TMB) are generally considered as the most important factors affecting the effectiveness of PD-1/PD-L1 blockade. The revolution in cancer immunotherapy achieved by PD-1/PD-L1 blockade offers the paradigm for scientific translation from bench to bedside. The next decades will without doubt witness the renaissance of immunotherapy.