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了解和克服T细胞耐受的策略，以此作为改进癌症和慢性病毒感染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受感染的细胞。过继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，努力利用这种能力治疗人类疾病。然而，这种治疗的预期临床益处对大多数患者来说还没有实现，这突显了对新的治疗方法的需要。成功的几个障碍已经被发现，包括在被转移的T细胞中缺失和诱导耐受，因为肿瘤抗原通常是异常或过度表达的自身抗原，受到外周自我耐受机制的保护。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(疲惫)，可以诱导耐受性，导致负性调节分子的表达，从而损害T细胞受体(TCR)信号。因此，虽然对自身免疫的保护至关重要，但耐受性对建立有效的CD8+T细胞免疫反应是一个实质性的挑战。尽管T细胞生物学和肿瘤免疫学取得了进展，但调节耐受性的分子机制在很大程度上仍不清楚，阻碍了克服体内耐受性用于治疗应用的努力。近年来，在转移的T细胞上诱导表达基因工程TCR(Dual-TCR)作为一种针对恶性或感染细胞的免疫反应已受到人们的广泛关注。这些双TCR T细胞不仅显示出作为治疗细胞试剂的前景，而且还作为工具更有效地询问耐受诱导的机制，耐受诱导至少部分由独立功能TCR复合体的近端缺陷而不是整体细胞缺陷调节。旨在从分子水平上了解双重表达的TCR如何相互影响和直接T细胞活性的实验，可能会为患者如何实现持久的治疗反应提供关键的见解。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，增强过继转移的T细胞对抗既定疾病的有效性和持久性，并利用这些细胞探索控制T细胞耐受诱导的细胞内事件。其具体目的是(1)挽救过继免疫治疗中耐受的肿瘤反应性CD8+T细胞；(2)阐明诱导CD8+T细胞耐受的分子机制；(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，并提供对T细胞耐受和拯救的机械性见解，以便这些方法可能被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.