Exploiting dual-TCR for rescue of CD8 T cell tolerance in adoptive immunotherapy

描述（由申请人提供）：我们的目标是探索旨在理解和克服T细胞耐受性的策略，作为改善癌症和慢性病毒感染的过继免疫治疗的一种方式。CD8+ T淋巴细胞是免疫系统的一个分支，负责识别和摧毁癌细胞或感染细胞。过继性T细胞免疫疗法通过将大量反应性T细胞转移到患者体内，努力利用这种能力来治疗人类疾病。然而，对于大多数患者来说，这种治疗的预期临床益处尚未实现，这突出了对新型治疗方法的需求。已经确定了成功的几个障碍，包括在转移的T细胞中缺失和诱导耐受性，因为肿瘤抗原通常是由外周自我耐受性机制保护的异常或过度表达的自身抗原。肿瘤微环境也通过不能向T细胞提供适当的共刺激信号来促进耐受性的诱导。此外，在慢性病毒感染期间，由于持续的过度刺激（衰竭），可诱导耐受性，导致负调节分子的表达，损害T细胞受体（TCR）信号传导。因此，尽管耐受性对抵抗自身免疫至关重要，但它对建立有效的CD8+ T细胞免疫应答构成了重大挑战。尽管在T细胞生物学和肿瘤免疫学方面取得了进展，但调节耐受性的分子机制在很大程度上仍然未知，这阻碍了克服治疗应用的体内耐受性的努力。最近，在转移的T细胞上诱导表达基因工程TCR（双TCR）作为一种指导对恶性或感染细胞的免疫反应的手段获得了热情。这些双TCR T细胞不仅有望作为治疗的细胞试剂，而且还可以作为更有效地询问耐受诱导机制的工具，这至少部分是由独立功能的TCR复合物的近端缺陷而不是全局细胞缺陷调节的。旨在在分子水平上了解双表达TCR如何相互影响并指导T细胞活性的实验可能为如何在患者中实现持久的治疗反应提供关键见解。本研究的长期目标是评估利用双tcr表达作为挽救T细胞耐受的手段的策略，提高过继转移T细胞对既定疾病的疗效和持久性，并利用这些细胞探索控制T细胞耐受诱导的细胞内事件。具体目的是：(1)拯救在过继免疫治疗中耐受的肿瘤反应性CD8+ T细胞；(2)阐明CD8+ T细胞耐受诱导调控的分子机制；(3)恢复慢性病毒感染时耗尽的CD8+ T细胞的功能。这些实验旨在研究免疫治疗的新途径，并提供T细胞耐受性和拯救的机制见解，以便这些方法可以转化为广泛的人类恶性肿瘤和感染。

DESCRIPTION (provided by applicant): Our goal is to explore strategies aimed at understanding and overcoming T cell tolerance as a way to improve adoptive immunotherapy for cancer and chronic viral infections. CD8+ T lymphocytes represent a branch of the immune system responsible for recognizing and destroying cancerous or infected cells. Adoptive T cell immunotherapy strives to harness this ability for the treatment of human disease by transferring large numbers of reactive T cells into patients. However, the anticipated clinical benefits of this treatment have not been realized for a majority of patients, highlighting the need for novel therapeutic approaches. Several obstacles to success have been identified including deletion and induction of tolerance in transferred T cells, as tumor antigens are often aberrantly or over-expressed self-antigens protected by mechanisms of peripheral self- tolerance. The tumor microenvironment also promotes the induction of tolerance by failing to provide appropriate co-stimulatory signals to T cells. Additionally, tolerance can be induced during chronic viral infections due to persistent over-stimulation (exhaustion), leading to expression of negative regulatory molecules that impair T cell receptor (TCR) signaling. Thus, while essential for protection against autoimmunity, tolerance represents a substantial challenge to mounting an effective CD8+ T cell immune response. Despite advances in T cell biology and tumor immunology, the molecular mechanisms that regulate tolerance remain largely unknown, hampering efforts to overcome in vivo tolerance for therapeutic applications. Recently, induced expression of genetically engineered TCR (dual-TCR) on transferred T cells has gained enthusiasm as a means to direct immune responses toward malignant or infected cells. These dual-TCR T cells have shown promise not only as cellular reagents for therapy, but also as tools to more effectively interrogate the mechanisms responsible for tolerance induction, which is regulated at least in part by proximal defects at independently functioning TCR complexes rather than global cellular defects. Experiments designed to understand at the molecular level how dually expressed TCR influence one another and direct T cell activity may provide key insight into how enduring therapeutic responses might be achieved in patients. The long-term objectives of this research are to evaluate strategies that exploit dual-TCR expression as means to rescue T cell tolerance, enhance the efficacy and durability of adoptively transferred T cells against established diseases, and to utilize such cells to explore the intracellular events that control induction of T cell tolerance. The specific aims are (1) to rescue tumor-reactive CD8+ T cells tolerized during adoptive immunotherapy; (2) to elucidate the molecular mechanisms that regulate induction of CD8+ T cell tolerance; and (3) to restore function of exhausted CD8+ T cells during chronic viral infection. These experiments are designed to examine new avenues of immunotherapy and provide mechanistic insight into T cell tolerance and rescue such that these approaches may be translated to a broad range of human malignancies and infections.