Redirecting T Cell Responses to Self/Tumor Antigens Using Enforced Costimulation

使用强制共刺激重定向 T 细胞对自身/肿瘤抗原的反应

• 批准号: 7800669
• 负责人: ADAM J ADLER
• 金额: $ 30.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800669
• 关键词: Address; American; Antigens; Autoantigens; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Model; Cell physiology; Clinical; Clinical Trials; Clonal Expansion; Couples; Data; Differentiation Antigens; Epitopes; Funding; Growth; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunosuppressive Agents; Individual; Inflammatory; Interleukin-2; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Mus; Pathway interactions; Peptides; Peripheral; Population; Principal Investigator; Process; Prostate; Prostatic Neoplasms; Reaction Time; Regimen; Role; Signal Transduction; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Translating; Tumor Antigens; Tumor Immunity; Tumor Tissue; Vaccination; Vaccines; anergy; base; cell type; clinically relevant; cytokine; immunogenic; interest; member; men; mouse model; novel; prevent; programs; public health relevance; response; success; tumor; vaccine efficacy

DESCRIPTION (provided by applicant): There has been considerable interest in developing vaccines to treat prostate cancer, the most common malignancy in American men. Nevertheless, efforts to translate vaccines developed in transplantable murine tumor models to treat human prostate cancer have only achieved limited success. During the initial funding period of this project we utilized a novel transgenic mouse model to demonstrate that the inability to achieve effective anti-prostate tumor immunity through vaccination is likely at least partially caused by the inactivation of tumor-reactive T cells through peripheral tolerization. To overcome T cell tolerance, we and others have targeted various costimulatory pathways to redirect the response of T cells encountering tolerogenic antigens. In particular, we found that enforced stimulation of CD134 (OX40) and CD137 (4-1BB) potently redirects CD8 T cells exposed to cognate soluble peptide to undergo massive clonal expansion and effector differentiation rather than anergy and deletion. Importantly, vaccines incorporating enforced OX40 and/or 4-1BB costimulation inhibit the growth of a variety of immunogenic murine tumors and are the basis for clinical trials to treat human cancers. We further tested the potential of enforced OX40/4-1BB dual costimulation to redirect T cell responses under highly stringent conditions where tolerizing epitopes derive from a widely and constitutively expressed parenchymal self-antigen. In contrast to soluble peptide, enforced dual costimulation boosted clonal expansion but surprisingly not effector differentiation when CD8 T cells encountered cognate parenchymally-derived self-antigen. CD4 T cells, which ironically possess a weaker tendency to undergo effector differentiation, expanded and differentiated into Th1 effectors in response to self-antigen plus enforced dual costimulation. Thus, specificity to self-antigen uncoupled effector differentiation from expansion exclusively in the CD8 T cell pool, and indicated that the response of CD8 T cells to enforced dual costimulation is strongly influenced by the APC presenting the tolerizing antigen. Nevertheless, when CD4 and CD8 T cells simultaneously encountered cognate parenchymal self-antigen during enforced dual costimulation, CD8 T cells were pushed to undergo effector differentiation. Thus, in the absence of CD4 T cell help enforced dual costimulation expands "harmless" self-reactive CD8 T cells. Notably, this expansion of "harmless" CD8 T cells is analogous to the decade-old but unexplained clinical observation that tumor-bearing individuals often harbor clonally expanded populations of anergic CD8 T cells specific for tissue/tumor- associated differentiation antigens. Our model thus represents a unique opportunity to understand and overcome this stubborn barrier to tumor immunity. The experimental aims of this revised competitive renewal application will elucidate the mechanism by which "harmless" CD8 T cells are expanded, and importantly how they can be pushed to express therapeutically useful effector functions in a clinically relevant prostate cancer model. PUBLIC HEALTH RELEVANCE: The efficacy of vaccines to treat cancer is hampered by immunosuppressive tolerance mechanisms that limit the function of tumor-reactive T lymphocytes. This project will utilize a novel model to understand the mechanisms that limit tumor-reactive T cell function, and importantly how these suppressive mechanisms can be overridden to enable T cell destruction of prostate tumors (the most common malignancy in American men).

描述（由申请人提供）：人们对开发治疗前列腺癌（美国男性最常见的恶性肿瘤）的疫苗非常感兴趣。然而，将在可移植鼠肿瘤模型中开发的疫苗转化为治疗人类前列腺癌的努力仅取得了有限的成功。在该项目的初始资助期间，我们利用一种新型转基因小鼠模型来证明，无法通过疫苗接种获得有效的抗前列腺肿瘤免疫可能至少部分是由于外周耐受导致肿瘤反应性 T 细胞失活所致。为了克服 T 细胞耐受性，我们和其他人针对各种共刺激途径来重定向 T 细胞遇到耐受性抗原的反应。特别是，我们发现强制刺激 CD134 (OX40) 和 CD137 (4-1BB) 可以有效地重定向暴露于同源可溶性肽的 CD8 T 细胞，使其经历大规模克隆扩增和效应分化，而不是无反应和缺失。重要的是，包含强制 OX40 和/或 4-1BB 共刺激的疫苗可抑制多种免疫原性小鼠肿瘤的生长，是治疗人类癌症的临床试验的基础。我们进一步测试了强制 OX40/4-1BB 双重共刺激在高度严格的条件下重定向 T 细胞反应的潜力，其中耐受表位源自广泛且组成型表达的实质自身抗原。与可溶性肽相反，当 CD8 T 细胞遇到同源的实质来源的自身抗原时，强制双重共刺激促进了克隆扩增，但令人惊讶的是没有效应分化。讽刺的是，CD4 T 细胞具有较弱的效应分化倾向，但在自身抗原和强制双重共刺激的作用下，CD4 T 细胞会扩增并分化为 Th1 效应细胞。因此，对自体抗原的特异性使效应细胞从仅在CD8 T细胞库中的扩增中分化出来，并表明CD8 T细胞对强制双重共刺激的反应受到呈递耐受抗原的APC的强烈影响。然而，当CD4和CD8 T细胞在强制双重共刺激期间同时遇到同源实质自身抗原时，CD8 T细胞被推动进行效应分化。因此，在缺乏 CD4 T 细胞的情况下，强制双重共刺激有助于扩大“无害”的自身反应性 CD8 T 细胞。值得注意的是，这种“无害”CD8 T 细胞的扩增类似于十年前但无法解释的临床观察结果，即携带肿瘤的个体通常含有克隆扩增的对组织/肿瘤相关分化抗原具有特异性的无反应性 CD8 T 细胞群。因此，我们的模型代表了理解和克服肿瘤免疫这一顽固障碍的独特机会。这一修订后的竞争性更新申请的实验目的将阐明“无害”CD8 T 细胞扩增的机制，以及重要的是如何推动它们在临床相关的前列腺癌模型中表达治疗上有用的效应器功能。 公共卫生相关性：免疫抑制耐受机制限制了肿瘤反应性 T 淋巴细胞的功能，从而阻碍了疫苗治疗癌症的功效。该项目将利用一种新模型来了解限制肿瘤反应性 T 细胞功能的机制，以及重要的是如何克服这些抑制机制以实现前列腺肿瘤（美国男性中最常见的恶性肿瘤）的 T 细胞破坏。