Mechanisms underlying focused ultrasound-induced immunogenicity in melanoma

Abstract

Abstract Advanced melanoma is an aggressive skin cancer with low survival rates. While the anti-tumor response relies on dendritic cells (DCs) to process tumor antigens, migrate to lymph nodes, and activate T-cells, within the tumor microenvironment (TME), DC activation is impeded. Subsequent immature DCs are a major mechanism underlying the ineffective T-cell response. We have shown that low-intensity focused ultrasound (LOFU), a novel therapy that delivers mechanical and thermal stresses to the tumor site, may enhance DC function in a B16 melanoma model. We hypothesize that LOFU enhances the dendritic cell-mediated anti-tumor response by inducing changes in tumor cell and dendritic cell autophagy and increasing pro-immunogenic factors in the TME.Autophagy is a lysosome-dependent process of cellular content degradation also implicated in the regulation of multivesicular body formation/degradation, and thus in the secretion of extracellular vesicles. Autophagy may subsequently modify the cargo of tumor-derived vesicles in a pro-immunogenic manner. We have found that LOFU treatment leads to increased LC3-II flux in melanoma cells and identified 82 proteins within melanoma-derived vesicles that are significantly enriched/reduced with LOFU, with enriched proteins partaking in processes such as antigen processing and intracellular trafficking. DCs pulsed with vesicles from LOFU-treated melanoma cells show enhanced activation of CD4 +and CD8 +T-cells, suggesting that LOFU may promote a DC-mediated anti-tumor response. Further understanding of DC involvement in the anti-tumor response will provide novel targets for the development of immunotherapies to improve survival and quality of life in advanced melanoma patients. Supported by grant from the NIH (R01 CA226861)