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）：开发疫苗以治疗前列腺癌，这是美国男性最常见的恶性肿瘤。然而，在可移植的鼠肿瘤模型中转化疫苗以治疗人前列腺癌的努力仅取得了有限的成功。在该项目的最初资助期间，我们利用了一种新型的转基因小鼠模型来证明无法通过外周耐受肿瘤反应性T细胞失活而无法通过疫苗接种来实现有效的抗疾病肿瘤免疫。为了克服T细胞的耐受性，我们和其他人针对各种共刺激途径，以重定向遇到耐受性抗原的T细胞的反应。特别是，我们发现对CD134（OX40）和CD137（4-1BB）的强制刺激有效地重定向CD8 T细胞暴露于同源可溶性肽中，以进行大规模的克隆扩张和效应子分化，而不是厌食和厌食。重要的是，结合了强制OX40和/或4-1BB共刺激的疫苗抑制了多种免疫原性鼠肿瘤的生长，并且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执行的OX40/4-1BB双重共刺激的潜力，以在高度严格的条件下重定向T细胞反应，在高度严格的条件下，耐受的表位源自广泛和组成式表达的实质自抗原。与可溶性肽相反，强制性双重共刺激增强了克隆扩张，但令人惊讶的是，当CD8 T细胞遇到同源实质衍生的自抗原时，没有效应子分化。具有讽刺意味的是，CD4 T细胞具有较弱的经历效应子分化的趋势，它响应于自我抗原和强制性双重共刺激而扩展并分化为Th1效应子。因此，仅在CD8 T细胞池中仅扩展的自我抗原未偶联效应子分化的特异性，并表明CD8 T细胞对实施双重共刺激的响应受到呈现耐受性抗原的APC的强烈影响。然而，当CD4和CD8 T细胞同时遇到在强制性双重共刺激期间同时遇到的相关实质自我抗原时，CD8 T细胞被推动以进行效应子分化。因此，在没有CD4 T细胞的情况下，有助于强制执行双重刺激会扩大“无害”的自反应性CD8 T细胞。值得注意的是，“无害” CD8 T细胞的这种扩展类似于十年但无法解释的临床观察结果，即含有肿瘤的个体通常具有针对组织/肿瘤相关分化抗原的厌氧CD8 T细胞的克隆膨胀群体。因此，我们的模型代表了理解和克服这种对肿瘤免疫力的顽固障碍的独特机会。这种经过修订的竞争性更新应用的实验目的将阐明“无害” CD8 T细胞扩展的机制，并且重要的是，如何推动它们在临床上相关的前列腺癌模型中表达治疗有用的效应子功能。 公共卫生相关性：疫苗治疗癌症的功效受到限制肿瘤反应性T淋巴细胞功能的免疫抑制耐受性机制的阻碍。该项目将利用一种新型模型来了解限制肿瘤反应性T细胞功能的机制，并且重要的是，如何覆盖这些抑制性机制，以使T细胞破坏前列腺肿瘤（美国男性最常见的恶性肿瘤）。