Separating autoimmunity and anti-tumor immunity

区分自身免疫和抗肿瘤免疫

基本信息

批准号：
9539082
负责人：
I. Caroline Le Poole
金额：
$ 36.91万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9539082
关键词：
Activated Lymphocyte Address Adoptive Transfer Adverse effects Amino Acids Animals Antibodies Antigen Presentation Pathway Antigens Attenuated Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Blindness CD8B1 gene Cell physiology Cells Clinic Clinical Consequentialism Cytotoxic T-Lymphocytes DNA Data Dendritic Cells Dendritic cell activation Detection Diarrhea Disease Environment Evolution Exanthema Family suidae Heat shock proteins Heat-Shock Proteins 70 Human Immune Immune Tolerance Immune response Immunotherapy In Vitro Intestinal Perforation Knockout Mice Lymphocyte Malignant Neoplasms Measures Mediating Membrane Modeling Modification Mus Normal tissue morphology Peptides Phenotype Physiology Pigments Predisposition Protein Isoforms Recruitment Activity Regressing Melanoma Reporting Site Skin Stress Surface T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Translational Research Tumor Antigens Tumor Immunity Tumor Tissue Uveitis Vaccinated Vaccines Variant Vitiligo Wild Type Mouse antitumor effect chimeric antigen receptor gene product graft vs host disease immune function in vivo melanoma migration mouse model mutant neoplasm immunotherapy neoplastic cell overexpression polarized cell prevent public health relevance receptor response screening stress protein transcriptome translational medicine treatment site tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Overexpression of inducible HSP70 (HSP70i) in tumors is exploited as a target for immunotherapy of melanoma and other cancers. HSP70i can also funnel external stress into an autoimmune response. As reported in Science Translational Medicine, we identified a peptide within HSP70i responsible for activating human dendritic cells (DCs) and developed HSP70iQ435A, a mutant DNA isoform with a single amino acid modification. The resulting gene product supports a tolerizing DC phenotype while preventing and even reversing autoimmunity in T cell receptor transgenic mice. T cells from treated mice, however, retain the ability to control melanoma once removed from the tolerizing environment and adoptively transferred into tumor bearing animals. DNA vaccinated mice also develop robust humoral responses to HSP70i that contain tumor growth. Protective responses were observed in CD8 knockout mice, and after adoptive B cell transfer to tumor challenged, wild-type mice. Our exciting preliminary data strongly suggest that HSP70iQ435A will suppress autoimmunity while supporting anti-tumor effects. The 'stressed' microenvironment within tumors leads to HSP70i overexpression that drives T cell recruitment and susceptibility to anti-HSP70 antibodies, whereas mutant HSP70 supports immune tolerance in the skin to prevent loss of normal pigment cells. We hypothesize that HSP70iQ435A polarizes DCs to support B cell responses to HSP70i surface expressed by tumor cells while preventing migration of MAA reactive T cells to normal tissues. Thus tumors are targeted by a combination of antibodies targeting the HSP70i c-terminus protruding from the membrane, and infiltrating T cells, while normal tissue cells are undisturbed through lack of HSP70i surface expression and reduced CTL recruitment. We will measure the ability of HSP70iQ435A to interfere with severe side effects of immunotherapy including graft versus host disease, and unravel the immune mechanism underlying divergent responses to HSP70iQ435A, addressing the consequences of treatment for the physiology and function of immune cells and their targets. A spontaneous swine model of melanoma and vitiligo is included to further the application of HSP70iQ435A.

描述（由申请人提供）：肿瘤中诱导型 HSP70 (HSP70i) 的过度表达被用作黑色素瘤和其他癌症免疫治疗的靶标，HSP70i 也可以将外部应激转化为自身免疫反应。 HSP70i 中的肽负责激活人类树突状细胞 (DC)，并开发了 HSP70iQ435A，一种突变 DNA产生的基因产物支持耐受性 DC 表型，同时预防甚至逆转接受治疗的小鼠的 T 细胞的自身免疫性，但一旦脱离耐受性环境，T 细胞仍保留控制黑色素瘤的能力。并过继转移到携带肿瘤的动物中，DNA 蘑菇小鼠也对包含肿瘤生长的 HSP70i 产生强烈的体液反应，并且在过继 B 细胞转移到受肿瘤攻击的野生型小鼠中观察到保护性反应。我们令人兴奋的初步数据强烈表明，HSP70iQ435A 将抑制自身免疫，同时支持抗肿瘤作用。肿瘤内的“应激”微环境导致 HSP70i 过度表达，从而驱动 T 细胞募集和对抗 HSP70 抗体的敏感性，而突变型 HSP70 支持免疫耐受。我们认为 HSP70iQ435A 会极化 DC，以支持 B 细胞对皮肤的反应。 HSP70i 由肿瘤细胞表面表达，同时阻止 MAA 反应性 T 细胞迁移到正常组织，因此，针对从膜突出的 HSP70i C 末端和浸润 T 细胞的抗体组合靶向肿瘤，而正常组织细胞则不受干扰。 HSP70i 表面表达缺乏和 CTL 募集减少我们将测量 HSP70iQ435A 干扰免疫治疗严重副作用（包括移植物抗宿主病）的能力。揭示对 HSP70iQ435A 不同反应的免疫机制，解决治疗对免疫细胞及其靶标的生理和功能的影响，包括黑色素瘤和白癜风的自发猪模型，以进一步促进 HSP70iQ435A 的应用。