Exploring the impact of HSP90 inhibition on antigen presentation and anti-tumor immune responses

项目摘要/摘要 旨在通过增强CD8 T细胞活性来刺激抗肿瘤免疫反应的免疫疗法 给癌症的治疗带来了革命性的变化，但许多患者没有反应。稳健的CD8 T细胞识别 肿瘤的发生需要细胞抗原在主要组织相容性复合体I(MHC-I)和 许多癌症抑制MHC-I递呈，作为逃避免疫检测和获得的一种手段 免疫治疗的抵抗力。这项提议概述了探索一种机械上独特的方法的实验 通过扰乱蛋白质折叠途径来刺激抗原呈递。热休克蛋白90 kDa 热休克蛋白90(HSP90)是一种分子伴侣，已知能调节多种细胞蛋白质的稳定性，称为 HSP90“客户”，包括参与致癌信号通路的蛋白质。也许最有趣的是， HSP90对于维持突变蛋白的构象稳定性尤为重要。因此， 抑制HSP90功能是破坏癌症突变蛋白质组稳定的独特策略 细胞将它们显示给免疫系统。虽然许多HSP90抑制剂已经在临床上被测试为 干扰致癌信号和杀死癌细胞的方法，还没有得到FDA的批准。初步数据 证明与临床测试的剂量策略相反，持续、低剂量暴露于HSP90 抑制物刺激MHC-I抗原递呈并驱动抗肿瘤免疫反应 通过一种从根本上不同于高剂量HSP90抑制剂治疗的机制来建立小鼠模型。 然而，MHC-I的诱导机制以及HSP90客户与MHC-I抗原的关系 是未知的。利用药理学、遗传学和蛋白质组学工具，这项提议将揭示这种机制。 驱动小剂量HSP90抑制剂治疗后MHC-I的诱导。此外，在基因方面的实验 基因工程小鼠的肺腺癌和结直肠癌模型将调查 这一治疗策略对抗原递呈和体内抗肿瘤免疫反应具有重要意义。总而言之，这是 研究将评估低剂量HSP90抑制作为诱导MHC-I抗原的机制不同的方法 向免疫系统呈递和揭示突变的癌细胞蛋白质组，并为 将口服生物可利用的HSP90抑制剂重新用于一类新的免疫调节剂。 这份提案还概述了职业目标和为获得教员职位做准备的目标。 值得注意的是，职业发展计划确定了在肿瘤免疫学、动物模型、 对学员的指导，以及口头和书面科学交流。培训活动旨在 培养运营独立实验室所需的科学和专业技能。最后， 麻省理工学院共同发起人、顾问团队和丰富的科学环境的互补专业知识是 特别适合确保拟议的研究和职业发展目标的成功。 好了！

Project Summary/Abstract Immunotherapies designed to stimulate anti-tumor immune responses by enhancing CD8+ T-cell activity have revolutionized the treatment of cancer, but many patients do not respond. Robust CD8+ T-cell recognition of tumors requires the presentation of cellular antigens on Major Histocompatibility Complex I (MHC-I) and many cancers suppress MHC-I presentation as a means of evading immune detection and acquiring resistance to immunotherapy. This proposal outlines experiments to explore a mechanistically distinct method of stimulating antigen presentation by disrupting protein-folding pathways. The heat shock protein 90 kDa (HSP90) is a molecular chaperone that is known to regulate the stability of numerous cellular proteins, termed HSP90 “clients”, including proteins involved in oncogenic signaling pathways. Perhaps most interestingly, HSP90 is particularly important for maintaining the conformational stability of mutated proteins. Therefore, inhibition of HSP90 function represents a unique strategy for destabilizing the mutant proteomes of cancer cells to reveal them to the immune system. While numerous HSP90 inhibitors have been tested clinically as a means to disrupt oncogenic signaling and kill cancer cells, none have been FDA approved. Preliminary data demonstrate that in contrast to clinically tested dosing strategies, continuous, low dose exposure to HSP90 inhibitors stimulates MHC-I antigen presentation and drives anti-tumor immune responses in a syngeneic mouse model through a mechanism that is fundamentally distinct from high dose HSP90 inhibitor treatment. However, the mechanism of MHC-I induction and the relationship between HSP90 clients and MHC-I antigens is unknown. Using pharmacological, genetic, and proteomic tools, this proposal will uncover the mechanism driving MHC-I induction following low dose HSP90 inhibitor treatment. Furthermore, experiments in genetically engineered mouse models of lung adenocarcinoma and colorectal cancer will investigate the consequences of this treatment strategy on antigen presentation and anti-tumor immune responses in vivo. Taken together, this study will evaluate low dose HSP90 inhibition as a mechanistically distinct method to induce MHC-I antigen presentation and reveal mutated cancer cell proteomes to the immune system, and also provide support for repurposing orally bioavailable HSP90 inhibitors as a new class of immunomodulatory agents. This proposal also outlines career objectives and goals in preparation for obtaining a faculty position. Notably, the career development plan identifies key areas for training in tumor immunology, animal modeling, mentorship of trainees, and oral and written scientific communication. The training activities are designed to build skills, both scientific and professional, that are required for running an independent laboratory. Finally, the complementary expertise of the co-sponsors, the advisory team, and rich scientific environment at MIT are uniquely suited to ensure success of the proposed research and career development goals. !