Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Simple Summary Metastatic prostate cancer (mPCa) is a well-known lethal condition. One of the mechanisms through which PCa cells become so aggressive is the avoidance of immune surveillance that further fosters cell growth, invasion, and migration. PD-L1/PD-1 axis plays a crucial role in inhibiting cytotoxic T cells and maintaining an immunosuppressive cancer microenvironment. Hence, targeting PD-L1/PD-1 axis represents a potential way to control mPCa. Unfortunately, mPCa patients do not respond to PD-L1/PD-1 axis blockade, focusing the research to understand the possible underpinning mechanisms. Our results provide a novel pathway taking part in cancer immunosurveillance escape and in the above-mentioned immunotherapy resistance, which provides the basis for additional studies aimed at developing novel therapeutic opportunities, possibly also in combination with antibodies blocking PD-L1/PD-1 axis. Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.

Automated summary

Metastatic prostate cancer (mPCa) is a lethal condition with no curative therapy available. Immunotherapeutic approaches targeting PD-L1 have been ineffective, highlighting the need to understand the mechanisms maintaining an immunosuppressive microenvironment contributing to tumor progression and resistance to PD-L1 inhibitors. The study identifies a novel pathway involving methylglyoxal and its metabolizing enzyme, glyoxalase 1, in promoting an immunosuppressive microenvironment and resistance to PD-L1 inhibitors in mPCa cells, suggesting potential therapeutic strategies to sensitize cells to immunotherapy.