Targeting ROS enzymes in myeloid-derived suppressor cell to enhance immunotherapy

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A recent breakthrough in treating melanoma patients is the use of immune checkpoint therapy (ICT). Unfortunately, the majority of patients do not respond to ICT. The limited success of ICT has, in large part, been due to the presence of a highly immunosuppressive melanoma microenvironment. Myeloid-derived suppressor cells (MDSCs), including tumor-associated neutrophils and tumor-associated macrophages, are critical drivers of this immunosuppressive microenvironment which promote tumor growth and evade the immune system. A major challenge in the identification of MDSCs is that the current phenotypic criteria using surface markers to characterize MDSCs overlaps with that used for myeloid cells, including neutrophils, macrophages and monocytes, thus, distinguishing this immunosuppressive subset of innate immune cells will be dependent upon functional characterization. The immunosuppressive nature of MDSCs are known to depend upon reactive oxygen species (ROS). MDSC respiratory burst is a major source of ROS which is primarily produced by the enzymes, myeloperoxidase (MPO) and NADPH oxidase 2 (NOX2). Thus, MPO and NOX2 may be important regulators of the immunosuppressive function of MDSCs. However, little is known with regards to the contribution of immunosuppressive MDSCs, particularly the function of ROS producing MPO and NOX2, in melanoma immunotherapy response and disease progression. This proposal aims to target the respiratory burst pathway in MDSCs to enhance ICT response and overcome the immunosuppressive tumor microenvironment. We hypothesize that increased MPO and NOX2 activity contributes to MDSC immunosuppression where the inhibition of MPO and NOX2 decreases MDSC immunosuppressive function enhancing ICT efficacy. In addition, MPO and NOX2 activity may emerge as novel functional markers of MDSC accumulation indicative of an immunosuppressive tumor microenvironment, and may be used as a predictive marker for ICT response. This project aims to identify the underlying drivers of MDSCs, specifically, that the immunosuppressive function of MDSCs is due to the elevated activity of the respiratory burst enzymes MPO and NOX2 which contribute to ICT resistance. Successful completion of this proposal would confirm that MPO and NOX2 are clinically-relevant targets and provide the framework for the clinical translation of MPO and NOX2 inhibitors as adjuvants for ICT to improve treatment response. MPO inhibitors, AZD5904, AZD4831 and Verdiperstat, are currently being evaluated in clinical trials for neurodegenerative disease. However, their effects in cancer have not been explored. This work would support the repurposed use of these MPO inhibitors as a combination therapeutic strategy to enhance ICT response in melanoma.