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

探索 HSP90 抑制对抗原呈递和抗肿瘤免疫反应的影响

• 批准号: 10554638
• 负责人: Alex Jaeger
• 金额: $ 24.4万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554638
• 关键词: Address; Advisory Committees; Animal Model; Antigen Presentation; Antigens; Area; Automobile Driving; CD8-Positive T-Lymphocytes; Cell surface; Cells; Client; Clinical; Clinical Data; Clinical Trials; Colonic Neoplasms; Colorectal Cancer; Communication; Complement; DNA; DNA Mismatch Repair Protein MSH2; Data; Detection; Development Plans; Dose; Ensure; Environment; Exposure to; FDA approved; Faculty; Fluorescence-Activated Cell Sorting; Genetic; Genetically Engineered Mouse; Goals; HSP 90 inhibition; Heat-Shock Proteins 90; Histology; I-antigen; Immune; Immune response; Immune system; Immunomodulators; Immunotherapy; Interferon Type II; Isogenic transplantation; Label; Laboratories; LoxP-flanked allele; Lung Adenocarcinoma; Lung Neoplasms; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Mentorship; Methods; Mismatch Repair Deficiency; Modeling; Molecular Chaperones; Molecular Conformation; Mus; Mutate; Mutation; Oncogenic; Oral; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Positioning Attribute; Preparation; Process; Proteins; Proteome; Proteomics; Relapse; Resistance; Running; Signal Pathway; Signal Transduction; Somatic Mutation; Stress; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Effect; Training; Training Activity; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; animal imaging; anti-tumor immune response; cancer cell; cancer therapy; career; career development; design; exome sequencing; experimental study; human disease; immune function; immunomodulatory therapies; in vivo; inhibitor; insight; mouse model; mutant; neoantigens; neoplastic cell; novel therapeutic intervention; peptide I; protein folding; research and development; response; skills; small molecule inhibitor; success; therapy design; tool; treatment strategy; tumor; tumor immunology

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. !

项目总结/摘要 通过增强CD 8 + T细胞活性刺激抗肿瘤免疫应答的免疫疗法 彻底改变了癌症的治疗方法，但许多患者没有反应。稳健的CD 8 + T细胞识别 肿瘤的发生需要在主要组织相容性复合物I（MHC-I）上呈递细胞抗原， 许多癌症抑制MHC-I呈递，作为逃避免疫检测和获得免疫应答的手段。 对免疫疗法的抵抗。该提案概述了探索一种机械上不同的方法的实验 通过破坏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（HSP 90）是一种分子伴侣，已知可调节多种细胞蛋白质的稳定性， HSP 90“客户”，包括参与致癌信号通路的蛋白质。也许最有趣的是， HSP 90对于维持突变蛋白的构象稳定性特别重要。因此，我们认为， 抑制HSP 90功能是使癌症突变蛋白质组不稳定的独特策略 将它们展示给免疫系统。虽然许多HSP 90抑制剂已被临床测试为 破坏致癌信号并杀死癌细胞的方法，没有一种得到FDA的批准。初步数据 证明与临床测试的给药策略相反，连续低剂量暴露于HSP 90 抑制剂刺激MHC-I抗原呈递，并在同基因组中驱动抗肿瘤免疫应答。 小鼠模型，其机制从根本上不同于高剂量HSP 90抑制剂治疗。 然而，MHC-I诱导的机制以及HSP 90客户与MHC-I抗原的关系尚不清楚。 不明利用药理学、遗传学和蛋白质组学的工具，这项提案将揭示其机制。 在低剂量HSP 90抑制剂处理后驱动MHC-I诱导。此外，基因实验 肺腺癌和结直肠癌的工程小鼠模型将研究 这种治疗策略对体内抗原提呈和抗肿瘤免疫反应有影响。总的来说，这 研究将评价低剂量HSP 90抑制作为诱导MHC-I抗原机制上不同的方法 向免疫系统展示和揭示突变的癌细胞蛋白质组，并为免疫系统提供支持。 重新利用口服生物可利用的HSP 90抑制剂作为一类新的免疫调节剂。 该提案还概述了职业目标和目标，为获得教师职位做准备。 值得注意的是，职业发展计划确定了肿瘤免疫学，动物建模， 指导受训人员，以及口头和书面科学交流。培训活动旨在 培养运行独立实验室所需的科学和专业技能。最后 共同赞助者的互补专业知识，咨询团队，以及麻省理工学院丰富的科学环境， 特别适合确保拟议的研究和职业发展目标的成功。 !