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

  • Luoyan AiEmail author
  • Antao Xu
  • Jie XuEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1248)

Abstract

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.

Keywords

PD-1 PD-L1 T cell inhibition Self-tolerance Cancer immune evasion 

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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Rheumatology, Renji HospitalShanghai Jiaotong UniversityShanghaiChina
  3. 3.Institutes of Biomedical Sciences, Zhongshan-Xuhui HospitalFudan UniversityShanghaiChina

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