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细胞增殖来促进肿瘤生长。 适应性免疫系统从安装有效的抗肿瘤反应。一个主要的后果是， 免疫抑制性肿瘤微环境是肿瘤抗原特异性T细胞耐受的诱导。 克服这种阻断仍然是癌症免疫治疗的主要挑战。我们的数据显示 由低强度聚焦超声（LOFU）诱导的热和物理应力防止了肿瘤的诱导， 抗原特异性T细胞耐受，并与消融治疗组合，导致原发性免疫缺陷综合征的控制改善。 黑色素瘤，减少局部复发，并显着降低肺转移的发生。这 代表了一种新的治疗方法，通过局部作用于肿瘤细胞， 肿瘤抗原特异性诱导T细胞耐受的建立。在这个应用程序中，我们的目标是了解 LOFU治疗后诱导增强的免疫原性黑素瘤细胞死亡的机制决定了 使用LOFU+消融作为原位黑色素瘤疫苗的潜力，并最终研究LOFU是否可以增加 当与检查点抑制剂组合使用时，效率和降低的毒性。

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.