Mechanistic study on synergistic photo-immunological effects of laser immunotherapy for metastatic cancers

项目摘要 转移导致治疗失败和90%的癌症相关死亡。我们已经研制出了激光 免疫疗法(LIT)治疗转移性癌症。LIT结合本地激光光热 新型免疫佐剂糖化壳聚糖治疗(PTT)和免疫治疗 全身抗肿瘤免疫反应。LIT在晚期转移癌的临床试验中取得了成功 传统治疗方式失败的癌症患者。具体地说，LIT已经证明了它的能力 以消除已治疗的原发肿瘤，并根除远处未治疗的转移瘤。然而， LIT的机制，特别是它如何控制肿瘤转移，目前还没有得到充分的研究。基于我们的 在以前的研究中，我们认为PTT和GC各自都能诱导独特的免疫反应，当 协同作用，产生系统的、长期的抗肿瘤免疫。具体地说，我们假设：1)PTT 诱导免疫原性肿瘤细胞死亡(ICD)，提供抗原源和损伤相关分子 触发宿主抗肿瘤免疫反应的模式(DAMP)；2)GC增强对 PTT诱导ICD产生的抗原，放大抗肿瘤T细胞反应；3)LIT协同和 增强PTT和GC诱导的免疫反应，特别是与其他 免疫疗法，如检查点抑制，提供有效的、系统的治疗效果，特别是在 肿瘤转移。为了验证这些假设，我们计划实现以下目标：(1)确定 PTT通过测定肿瘤组织中的温度分布和通过 PTT所致ICD和DAMPS的特征；(2)确定GC对免疫系统的影响 在LIT期间，特别是T细胞的激活以及抗原摄取和提呈的增强；以及 (3)确定LIT以及LIT和检查点抑制的组合对 增强肿瘤免疫原性，控制肿瘤转移。成功地完成这项工作 项目将达到以下目标：(1)全面了解免疫学 LIT消除和抑制转移的机制；(2)为LIT的发展奠定必要的基础 成为各种转移性癌症患者的有效治疗方式；(3)促进 开发使用协同免疫机制的新的、新的治疗策略 LIT与其他辅助疗法相结合，用于转移性癌症患者。

Project Summary Metastasis causes treatment failure and 90% of cancer-related deaths. We have developed laser immunotherapy (LIT) for the treatment of metastatic cancers. LIT combines local laser photothermal therapy (PTT) and immunotherapy using glycated chitosan (GC), a novel immunoadjuvant, to induce systemic antitumor immune responses. LIT has shown success in clinical trials for late-stage, metastatic cancer patients who had failed conventional treatment modalities. Specifically, LIT has demonstrated its ability to eliminate treated primary tumors and eradicate untreated metastases at distant sites. However, the mechanism of LIT, particularly how it controls tumor metastases, has not been fully investigated. Based on our previous studies, we believe that PTT and GC each induces unique immunological reactions, which, when synergized, produce a systemic, long-term antitumor immunity. Specifically, we hypothesize that: 1) PTT induces immunogenic tumor cell death (ICD), providing antigen sources and damage-associated molecular patterns (DAMPs) to trigger host antitumor immune responses; 2) GC enhances uptake and presentation of antigens generated by PTT-induced ICD, amplifying antitumor T cell response; and 3) LIT synergizes and amplifies the immune responses induced by PTT and GC, particularly when combined with other immunotherapies, such as checkpoint inhibition, providing potent, systemic therapeutic effects, especially on tumor metastases. To test these hypotheses, we plan to achieve the following aims: (1) to determine the photothermal-immunological effects of PTT by determining temperature distribution in tumor tissue and by characterizing the ICD and DAMPs generated by PTT; (2) to determine the effects of GC on immune system during LIT, particularly on activation of T cell as well as enhancement of antigen uptake and presentation; and (3) to determine the effects of LIT, as well as the combination of LIT and checkpoint inhibition, on the enhancement of tumor immunogenicity and on controlling tumor metastasis. The successful completion of this project will achieve the following goals: (1) to obtain a comprehensive understanding of the immunological mechanism of LIT in eliminating and inhibiting metastases; (2) to lay the foundation necessary to advance LIT into an effective treatment modality for patients with a variety of metastatic cancers; (3) to facilitate the development of new, novel treatment strategies using synergistic immunological mechanisms similar to that of LIT, in combination with other complementary therapies, for patients with metastatic cancers.