Abstract 1851: Mechanisms underlying focused ultrasound-induced immunogenicity in melanoma

Abstract

Abstract Advanced melanoma is an aggressive skin cancer characterized by low survival rates. The generation of a robust anti-tumor response relies on dendritic cells (DCs) to process tumor antigens, migrate to draining lymph nodes, and activate T-cells. Within the tumor microenvironment, immunosuppressive factors impede DC differentiation and activation, and the subsequent immature DC phenotype is a major mechanism underlying the ineffective T-cell response in melanoma patients. We have shown that low-intensity focused ultrasound (LOFU), a novel therapy that delivers mechanical and thermal stresses locally at the tumor site, may enhance DC function in a B16 murine 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 that has previously been 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 extracellular vesicles, such as exosomes, in a pro-immunogenic manner. We have found that LOFU treatment is associated with an increase in autophagic flux in melanoma cells and have identified at least 82 proteins within melanoma-derived extracellular vesicles that are significantly enriched or reduced with LOFU treatment, with enriched proteins partaking in essential processes including antigen processing, intracellular trafficking, and cellular metabolism. DCs pulsed with vesicles from LOFU-treated melanoma cells have shown enhanced activation of both CD4+ and CD8+ T-cell activation, suggesting that the LOFU-induced increase in tumor cell autophagy and modification of vesicular cargo may promote a DC-activated anti-tumor antigen activation response. Characterization of other mechanisms by which LOFU may enhance DC function, such as direct changes in DC autophagy, is critical to elucidate DC-mediated pathways involved in the 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. Citation Format: Sandra Pelka, Sanmay Bandyopadhyay, Sanjay Pandey, Chandan Guha, Fernando Macian. Mechanisms underlying focused ultrasound-induced immunogenicity in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1851.