Use of focused ultrasound to increase melanoma immunogenicity and inhibit tumor-induced T cell tolerance

肿瘤微环境中的免疫抑制机制通过阻止肿瘤生长促进肿瘤生长 适应性免疫系统不会产生有效的抗肿瘤反应。经济衰退的主要后果之一是 免疫抑制的肿瘤微环境是诱导肿瘤抗原特异性T细胞耐受的机制。 克服这种障碍仍然是癌症免疫治疗中的一大挑战。我们的数据显示 低强度聚焦超声(LOFU)引起的热应激和物理应激可预防肿瘤的诱发 抗原特异性T细胞耐受性，并与消融治疗相结合，结果改善了对初发 黑色素瘤，减少局部复发，并显著减少肺转移的发生。这 代表了一种新的治疗方法，通过局部作用于肿瘤细胞，有可能抑制 肿瘤抗原特异性诱导T细胞耐受模型的建立在本应用程序中，我们的目标是了解 LOFU治疗后诱导免疫原性黑色素瘤细胞死亡的机制决定了 LOFU消融作为原位黑色素瘤疫苗的可能性及最终研究LOFU能否增加 与检查点抑制剂联合使用时，可提高效率并降低毒性。

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.