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

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）的疫苗有相当大的兴趣。然而，将在可移植的鼠肿瘤模型中开发的疫苗转化为治疗人前列腺癌的努力只取得了有限的成功。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，通过疫苗接种无法实现有效的抗前列腺肿瘤免疫可能至少部分是由外周耐受化导致的肿瘤反应性T细胞失活引起的。为了克服T细胞耐受性，我们和其他人已经靶向了各种共刺激途径以重定向T细胞遇到致耐受性抗原的应答。特别地，我们发现CD 134（0X 40）和CD 137（4-1BB）的强制刺激有效地重定向暴露于同源可溶性肽的CD 8 T细胞以经历大规模克隆扩增和效应分化，而不是无反应性和缺失。重要的是，包含强制OX 40和/或4-1BB共刺激的疫苗抑制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。我们进一步测试了在高度严格的条件下强制OX 40/4-1BB双重共刺激重定向T细胞应答的潜力，其中耐受性表位来源于广泛和组成型表达的实质自身抗原。与可溶性肽相反，当CD 8 T细胞遇到同源实质来源的自身抗原时，强制性双重共刺激促进克隆扩增，但令人惊讶地不是效应分化。具有讽刺意味的是，CD 4 T细胞具有较弱的效应分化倾向，在自身抗原加强制双重共刺激的作用下扩增并分化为Th 1效应细胞。因此，特异性自身抗原解偶联效应分化从扩展排他地在CD 8 T细胞池中，并表明，CD 8 T细胞的反应，以加强双重共刺激的APC呈递耐受性抗原的强烈影响。然而，当CD 4和CD 8 T细胞同时遇到同源的实质自身抗原在强制双共刺激，CD 8 T细胞被推到经历效应分化。因此，在缺乏CD 4 T细胞的情况下，辅助性双重共刺激扩增了“无害的”自身反应性CD 8 T细胞。值得注意的是，“无害”CD 8 T细胞的这种扩增类似于十年前但无法解释的临床观察，即携带肿瘤的个体通常具有对组织/肿瘤相关分化抗原特异性的无反应性CD 8 T细胞的克隆扩增群体。因此，我们的模型代表了一个独特的机会，以了解和克服这一顽固的肿瘤免疫障碍。这项修订后的竞争性更新申请的实验目的将阐明“无害”CD 8 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机制的阻碍。该项目将利用一种新的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，使前列腺肿瘤（美国男性最常见的恶性肿瘤）的T细胞破坏。

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).