Abstract
New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.
Highlights
Unlike immunologically “hot” tumors such as lung cancer, melanoma, and bladder cancer, most breast carcinomas are not inherently immunogenic
We provide the first demonstration that RSV targets the immune evasion capacities of cancer cells by directly disrupting N-glycan branching and promoting dimerization of programmed death ligand-1 (PD-L1), thereby impeding the correct localization of PD-L1 to the plasma membrane, preventing the PD-1 interaction surface of PD-L1 and, increasing the susceptibility of biologically aggressive cancer cells to T-cell-mediated cell death (Figure 9)
The ability of RSV to generate a high mannose, abnormally glycosylated form of PD-L1 does not rely on its SIRT1-activating activity and appears not to involve the well-known capacity of RSV to activate a www.aging-us.com positive feedback between AMPK and SIRT1 [78,79,80]
Summary
Unlike immunologically “hot” tumors such as lung cancer, melanoma, and bladder cancer, most breast carcinomas are not inherently immunogenic They typically exhibit low T-cell infiltration and are unlikely to benefit from immune checkpointcentric therapies [1,2,3,4,5]. Exceptions to this immunologically “cold” rule of breast carcinomas are the socalled basal-like [6,7,8,9,10,11,12,13,14] and HER2-positive [15,16,17,18,19,20] subtypes, both of which show evidence of immunogenicity including tumor immune infiltrates and stromal and intratumoral tumor-infiltrating lymphocytes, a good predictive marker for responses to immunotherapy. The identification of new strategies to block the immune-inhibitory signal of PD-L1 in basal-like and HER2-positive subtypes is urgently needed
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