The intracellular signalosome of PD-L1 in cancer cells

Abstract

Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progression. PD-L1 possesses two main pro-oncogenic functions. First, PD-L1 is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the inhibitory receptor PD-1. Second, PD-L1 function relies on the delivery of intrinsic intracellular signals that enhance cancer cell survival, regulate stress responses and confer resistance toward pro-apoptotic stimuli, such as interferons. Here, we review the current knowledge on intracellular signal transduction pathways regulated by PD-L1, describe its associated signalosome and discuss potential combinations of targeted therapies against the signalosome with PD-L1/PD-1 blockade therapies.

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy

“…Reports of tumor-intrinsic signaling pathways induced by programmed death ligand 1 (PD-L1) have emerged, linking PD-L1 with the promotion of epithelial-to-mesenchymal transition (EMT), stimulation of the mTOR/AKT antiapoptotic pathway, as well as inhibition of IFN-dependent apoptosis (22)(23)(24). Whereas each of these pathways may be protumorigenic, there are no known associations between PD-L1 and the induction of adaptive resistance to anti-PD-1 Ab immunotherapy via the stimulation of tumor-intrinsic signaling pathways.…”

Liquid Biopsy as Novel Tool in Precision Medicine: Origins, Properties, Identification and Clinical Perspective of Cancer’s Biomarkers

“…First, PD-L1 is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the inhibitory receptor PD-1. Second, PD-L1 function relies on the delivery of intrinsic intracellular signals that enhance cancer cell survival, regulate stress responses and confer resistance toward pro-apoptotic stimuli, such as interferons [60]. PD-L1 expression was detected in the plasma ctRNA of all cancer types at varying frequencies but no PD-L1 messenger RNA (mRNA) was detected in cancer-free individuals there was a high degree of concordance between expression of PD-L1 protein in tumor tissues and PD-L1 gene expression in plasma, and both methods were equally predictive of pharmacological response.…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…In the early 2000s, and decades after its discovery and cloning, PD-1, along with its ligand PD-L1, was identified as a regulator of T cell activation and immune exhaustion (118). In peripheral tissues, PD-1 -expressing T cells interact with immunosuppressive PD-1 ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) found on tumor cells, stromal cells, or both (119)(120)(121)(122).…”