The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

Abstract

Programmed death-ligand 1 (PD-L1) is an immune checkpoint inhibitor that binds to its receptor PD-1 expressed by T cells and other immune cells to regulate immune responses; ultimately preventing exacerbated activation and autoimmunity. Many tumors exploit this mechanism by overexpressing PD-L1 which often correlates with poor prognosis. Some tumors have also recently been shown to express PD-1. On tumors, PD-L1 binding to PD-1 on immune cells promotes immune evasion and tumor progression, primarily by inhibition of cytotoxic T lymphocyte effector function. PD-1/PD-L1-targeted therapy has revolutionized the cancer therapy landscape and has become the first-line treatment for some cancers, due to their ability to promote durable anti-tumor immune responses in select patients with advanced cancers. Despite this clinical success, some patients have shown to be unresponsive, hyperprogressive or develop resistance to PD-1/PD-L1-targeted therapy. The exact mechanisms for this are still unclear. This review will discuss the current status of PD-1/PD-L1-targeted therapy, oncogenic expression of PD-L1, the new and emerging tumor-intrinisic roles of PD-L1 and its receptor PD-1 and how they may contribute to tumor progression and immunotherapy responses as shown in different oncology models.

Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells

“…ICIs against the programmed death-1 (PD-1, CD279) and its ligand, is an important focus in cancer immunology and oncology with FDA approval for various types of cancer. Immunotherapies targeting PD-1/programmed death-ligand 1 (PD-L1) signaling have now become the first-line treatment for some cancers due to their promotion of anti-tumor immune responses in patients with advanced cancers[ 14 ].…”

“…PD-L1 is a 40-kDa type I transmembrane protein, which is expressed in immune cells (ICs) such as T cells, B cells, NK cells, DCs, macrophages, and myeloid-derived suppressor cells. It is also expressed in non-IC types including epithelial, endothelial, and tumor cells[ 14 , 23 ].…”

“…The PD-1/PD-L1 axis plays an important role in successful protective cellular immune response and prevention of immune overstimulation and autoimmune disorders through maintenance of T cell homeostasis and control of self-tolerance[ 14 , 36 , 38 ] (adapted in Figure 1 ). PD-L1 binding to PD-1 leads to the inhibition of T cell functional activation by: (1) Directly targeting the T cell receptor (TCR) signaling through phosphatases recruitment and inhibition of ZAP70 and PI3K downstream pathways; (2) Indirectly inhibiting TCR signaling and T cell proliferation by regulating CK2 expression and activation; (3) Regulating TCR surface expression by promoting E3 ubiquitin ligases expression, leading to TCRs removal from the T cell surface and loss of T cell response upon antigen stimulation; and (4) Altering T cell metabolism by inhibition of ERK and PI3K/Akt activities, resulting in a long-lived memory T cells phenotype[ 32 , 34 ].…”

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…siRNA has emerged as a powerful approach for cancer immunotherapy [68]. siRNA can target different molecules, such as programmed cell death-1 (PD-1) and its ligand (PD-L1), as well as interleukin 10 receptor, STAT3, and transforming growth factor-β receptor, on the surface of immune cells and/or tumor cells, which participate actively in the process of immune activation, to lessen tumor evasion from the host's immune system and boost the immune response against tumors [69][70][71][72]. Consistently, myeloid-derived suppressor cells (MDSC) are recognized as imperative inhibitors of T-cell responses in numerous malignancies, including PCa.…”

Association Between PDL1 Genetic Variation and Efficacy of Apatinib Monotherapy in Patients with Previously Treated Advanced NSCLC: A Real-World Retrospective Study

“…PDL1 is one of the most important biomarkers for the prognostic prediction of immunotherapy. 14 A study has shown that higher PDL1 expression predicts superior clinical outcome with P D1/ P DL 1 inhibitors. 15 Although patients with positive PDL1 expression can benefit from P D1/ P DL 1 inhibitors, the association between the prognosis of patientsadministered antiangiogenic targeted drugs and PDL1 expression status remains unknown.…”