Immunosuppressive mechanisms in the tumor microenvironment promote tumor growth by preventing the adaptive immune system from mounting effective antitumor responses. One of the main consequences of the immunosuppressive tumor microenvironment is the induction of tumor antigen-specific T cell tolerance. Overcoming such blockade has remained a major challenge in cancer immunotherapy. Our data show that thermic and physical stress induced by low-intensity focused ultrasound (LOFU) prevents the induction of tumor- antigen specific T cell tolerance and, in combination with ablative therapy, results in improved control of primary melanoma, reduces local recurrence and markedly decreases the occurrence of pulmonary metastases. This represents a new therapeutic approach that by acting locally on tumor cells has the potential to inhibit the establishment of tumor-antigen specific induced T cell tolerance. In this application, our goal is to understand the mechanisms that induce enhanced immunogenic melanoma cell death after LOFU-treatment, determine the potential of using LOFU+ablation as an in-situ melanoma vaccine and finally study whether LOFU can increase efficiency and reduced toxicity when used in combination with checkpoint inhibitors.
We have recently shown that a novel therapeutic approach using low energy ultrasound can be used to induce activation of T cells to more efficiently mount responses against melanoma cells. In this proposal, we seek to understand the mechanisms that account for this effect and define novel combinatorial therapies that can be used to generate in-situ cancer vaccines and to boost efficacy and increased specificity of immunotherapy approaches to treat melanoma. We expect that these studies will set the basis to delineate novel immunomodulatory pathways and generate new protocols that can eventually be translated into the clinic to treat melanoma.
