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

描述（由申请人提供）：对于开发用于治疗前列腺癌（美国男性最常见的恶性肿瘤）的疫苗有相当大的兴趣。然而，将在可移植小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只取得了有限的成功。在本项目的初始资助阶段，我们利用一种新的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肿瘤反应性T细胞通过外周耐受失活引起的。为了克服T细胞的耐受性，我们和其他人已经针对各种共刺激途径来重新定向T细胞遇到耐受性抗原的反应。特别是，我们发现CD134 （OX40）和CD137 （4-1BB）的强制刺激可以有效地重新引导暴露于同源可溶性肽的CD8 T细胞进行大量克隆扩增和效应分化，而不是能量和缺失。重要的是，结合强制OX40和/或4-1BB共刺激的疫苗可以抑制多种免疫原性小鼠肿瘤的生长，这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双重共刺激的潜力，以在高度严格的条件下重新定向T细胞反应，其中耐受性表位来自广泛且组成性表达的实质自身抗原。与可溶性肽相比，当CD8 T细胞遇到同源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。具有讽刺意味的是，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下，CD4 T细胞扩增并分化为Th1效应细胞。因此，对CD8 T细胞池中自身抗原解耦效应分化的特异性表明，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中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细胞帮助的情况下，强制双重共刺激扩大了“无害的”自反应性CD8 T细胞。值得注意的是，这种“无害”CD8 T细胞的扩增与十年前的临床观察类似，但无法解释的是，肿瘤携带个体经常携带无性扩增的无能CD8 T细胞群，这些细胞对组织/肿瘤相关分化抗原具有特异性。因此，我们的模型代表了一个独特的机会来理解和克服这种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”CD8 T细胞扩增的机制，以及重要的是如何在临床相关的前列腺癌模型中推动它们表达治疗有用的效应功能。

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).