Abstract 3868: Decreased metastatic burden in a spontaneous metastatic melanoma model by inhibiting myeloid-derived suppressor cell function

Abstract Metastatic melanoma is the leading cause of skin cancer-related deaths, with a five-year survival rate of only 30%. Myeloid derived suppressor cells (MDSCs) are considered a driver of metastatic progression, supporting pre-metastatic niche formation, facilitating tumor cell migration, invasion, and extravasation and promoting immune evasion. This study evaluates the contribution of myeloperoxidase (MPO) and extracellular trap formation in melanoma metastasis. Using a spontaneous melanoma metastasis model, we demonstrate metastases in the lungs, bone, and lymph node approximately 4 weeks post surgical resection of primary subcutaneous B16F10 tumors. Tumor growth and metastatic burden were quantified using a bioluminescent reporter stably expressed in B16F10 cells. Syngeneic myeloperoxidase-deficient and peptidyl arginine deiminase 4 (PAD4)-deficient mice, as well as C57BL/6J wild-type mice treated with an MPO-specific inhibitor or hydroxychloroquine (an extracellular trap inhibitor), exhibited significantly reduced lung and bone metastases compared to untreated wild-type controls. PAD4, a critical enzyme in extracellular trap formation, was essential for these effects. Targeting myeloperoxidase or extracellular traps significantly reduced MDSC populations while increasing B cells in the metastatic microenvironment, as assessed by flow cytometry. Ex vivo assays revealed diminished MDSC-mediated suppression of T and B cells when myeloperoxidase or extracellular trap formation was inhibited. Notably, depletion of B cells abrogated the anti-metastatic effects of targeting myeloperoxidase or extracellular traps, highlighting B cells as central mediators of metastasis suppression. These findings demonstrate that targeting myeloperoxidase or extracellular trap formation reduces metastatic burden and mitigates MDSC-mediated pro-metastatic and immunosuppressive functions. This work underscores the therapeutic potential of targeting myeloperoxidase and extracellular trap formation in combating melanoma metastasis. Citation Format: Kaitlyn M. Landreth, Angisha Basnet, Mary Garland-Kledzik, Brian A. Boone, Tracy W. Liu. Decreased metastatic burden in a spontaneous metastatic melanoma model by inhibiting myeloid-derived suppressor cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3868.