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（由适用提供）：探讨了肿瘤中诱导HSP70（HSP70I）的过表达，作为黑色素瘤和其他癌症免疫疗法的靶标。 HSP70I还可以将外部压力汇到自身免疫反应中。正如科学转化医学所报道的那样，我们在HSP70I中鉴定了一个负责激活人树突状细胞（DC）的肽，并开发了HSP70IQ435A，这是一种具有单个氨基酸修饰的突变DNA同工型。所得的基因产物支持耐受性直流表型，同时预防T细胞受体转基因小鼠的自身免疫性，甚至逆转自身免疫性。然而，来自处理过的小鼠的T细胞保留了控制黑色素瘤一旦从耐受环境中去除并自适应地转移到肿瘤轴承动物中的能力。 DNA接种小鼠还会对含有肿瘤生长的HSP70I产生强大的体液反应。保护性反应我们在CD8敲除小鼠中观察到了我们，在收养B细胞转移到肿瘤后，野生型小鼠。我们令人兴奋的初步数据强烈表明HSP70IQ435A将抑制自身免疫性，同时支持抗肿瘤效应。肿瘤内的“压力”微环境导致HSP70I过表达，从而驱动T细胞募集和对抗HSP70抗体的敏感性，而突变的HSP70则支持皮肤中的免疫耐受性，以防止正常色素细胞损失。我们假设HSP70IQ435A偏振DC，以支持B细胞对肿瘤细胞表达的Hsp70i表面的反应，同时又可以防止MAA反应性T细胞迁移到正常组织。肿瘤是由靶向HSP70I C末端突出膜和浸润T细胞的抗体组合的，而正常组织细胞由于缺乏HSP70I表面表达和降低CTL募集而受到正常组织细胞的影响。我们将衡量HSP70IQ435A干扰免疫疗法的严重副作用，包括移植物与宿主疾病，并揭示对HSP70IQ435A的不同反应的免疫力学，从而解决了对免疫学及其靶标的治疗的后果。包括黑色素瘤和白癜风的赞助猪模型，以进一步应用HSP70IQ435A。