Mechanisms of Durable Antitumor Immunity Mediated by PI3K-targeted T cells

PI3K 靶向 T 细胞介导的持久抗肿瘤免疫机制

• 批准号: 10682190
• 负责人: Chrystal Mary Paulos
• 金额: $ 63.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-07 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682190
• 关键词: Ablation; Address; Adoptive Cell Transfers; Adoptive Transfer; Animals; Antigen Targeting; Autoimmune; Bioenergetics; Biogenesis; Cancer Patient; Cells; Cellular Metabolic Process; Clinical; Collaborations; Complement; Cytoprotection; Data; Endowment; Engineering; Engraftment; Enzymes; Future; Genetic; Height; Human; Immunity; Immunotherapy; Impairment; In Vitro; Infection; Investigation; Lung; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Lung; Mitochondria; Monitor; Mus; Neoplasm Metastasis; PIK3CG gene; Pathway interactions; Patients; Phenotype; Primary Neoplasm; Property; Protein Isoforms; Publications; RNA; Recurrent tumor; Reporting; Research; Role; Signal Pathway; Signal Transduction; Skin; Solid Neoplasm; Supporting Cell; Surgical Oncology; System; T cell therapy; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Translational Research; Tumor Antigens; Tumor Immunity; Tumor Tissue; Viral; Vitiligo; Work; antigen-specific T cells; cancer immunotherapy; cancer therapy; chimeric antigen receptor T cells; clinically relevant; defined contribution; empowerment; exhaustion; fighting; improved; in vivo; inhibitor; innovation; insight; melanoma; mesothelin; mouse model; novel; novel strategies; oligoribonuclease; overexpression; pancreatic neoplasm; pharmacologic; response; side effect; stem; stemness; transcriptome sequencing; translational impact; tumor; tumor eradication; tumor metabolism; unpublished works

Project Summary The metabolic properties of T cells can influence their ability to mount effective responses against solid tumors. This limitation is particularly relevant to optimal adoptive cell therapy approaches, whereby tumor-antigen targeted T cells are administered to patients to eradicate tumors. Our team has made great progress towards overcoming this issue via our discovery that selective blockade of the PI3K p110δ isoform with CAL-101 (Idealisib®) in vitro can rewire the metabolism of T cells and render them potent upon in vivo administration to tumor bearing mice. Importantly, the durability of these T cells is associated with their enhanced mitochondrial bioenergetics and persistence, and an extraordinary capacity to mount rapid recall responses against tumor re- challenge. While mice are cured from this therapy, they often develop autoimmune vitiligo. Our newest data reveal that while PI3Kδ-inhibited T cells have stemness properties in vitro, they become tissue-resident and effector memory cells in lymphoid tissues. These provocative results imply that they may cooperate to sustain host-wide protection against metastasis by virtue of their memory phenotype and elicit vitiligo in the animal. We conducted RNAseq on these potent PI3Kδ-inhibited T cells and identified a novel oligoribonuclease, called REXO2. Our preliminary data indicates that genetic ablation of REXO2 abrogates their ability to fight tumors, but overexpressing REXO2 supports mitochondrial biogenesis, antitumor metabolism and endows T cells with efficacy as an adoptive cell therapy. These innovative data are the first to define a role for REXO2 as an actionable factor to enhance ACT. This proposal will uncover mechanisms supporting T cell metabolism and immunity in the context of REXO2 and PI3K signaling and facilitate future translational efforts for ACT with REXO2-manipulated human T cells. We hypothesize REXO2 supports metabolism of antitumor T cells and that REXO2 can be leveraged in T cells to improve the efficacy of ACT. The role of REXO2 in T cells and its therapeutic potential will be investigated in three complementary Specific Aims: AIM 1 will identify mechanisms by which PI3Kδ targeting supports antitumor T cell activity, by studying how REXO2—induced via PI3Kδ- blockade—bolsters bioenergetics to instill immunity in mice. AIM 2 will define how resident and lymphoid memory donor T cells protect mice from metastasis. Studies will also test how REXO2, sustained preferentially in skin- resident donor T cells, impacts immunity to self-versus tumor tissues. We will use human TIL and CAR T cell products generated in cancer patients and clinically-relevant xenogeneic human tumor mouse models in AIM 3, inspired by our desire to delve into studies with immediate translational significance. Namely, this work provides foundational data to generate optimized, redirected human T cells with heighted REXO2. This approach is attractive to augment immunometabolism in poorly functional T cells and empower them to mediate durable memory responses to solid tumors. Overall, the proposed research is significant, as it is expected to reveal that manipulation of REXO2 can safely protect against tumor recurrence with reduced side effects to patients.

项目摘要 T细胞的代谢特性会影响其对实体瘤的有效反应的能力。 该限制与最佳自适应细胞疗法方法特别相关，从而使肿瘤抗原 将靶向T细胞施用对放射性肿瘤的患者进行。我们的团队取得了长足的进步 通过发现PI3Kp110Δ同工型的选择性阻断与CAL-101的选择性封锁，克服了这个问题 （Idealisib®）体外可以重新连接T细胞的代谢，并使它们在体内给药上有效 肿瘤轴承小鼠。重要的是，这些T细胞的耐用性与它们增强的线粒体有关 生物能学和持久性，以及针对肿瘤的快速回忆反应的非凡能力 挑战。在这种疗法中治愈小鼠时，它们经常会产生自身免疫性白斑。我们的最新数据 揭示虽然PI3Kδ抑制的T细胞在体外具有干性特性，但它们成为组织居民，并且 淋巴组织中的效应记忆细胞。这些挑衅性的结果暗示它们可以协调以维持 宿主在整个转移中的保护，凭借其记忆表型并在动物中引起白癜风。我们 在这些潜在的PI3Kδ抑制的T细胞上进行了RNASEQ，并确定了一种新型的寡核酸酶，称为 rexo2。我们的初步数据表明，REXO2的遗传消融消除了它们与肿瘤作斗争的能力，但 过表达的REXO2支持线粒体生物发生，抗肿瘤代谢，并赋予T细胞 作为一种适应性细胞疗法的功效。这些创新数据是第一个将Rexo2角色定义为 可行的因素增强行为。该建议将发现支持T细胞代谢的机制和 在REXO2和PI3K信号传导的背景下的免疫力​​，并促进了将来的转化努力 REXO2操纵的人T细胞。我们假设REXO2支持抗肿瘤T细胞的代谢，并且 REXO2可以在T细胞中利用，以提高ACT的效率。 Rexo2在T细胞及其ITS中的作用 治疗潜力将以三个完整的特定目的进行研究：AIM 1将确定机制 PI3Kδ的靶向通过研究通过PI3KΔ-诱导的RexO2如何支持抗肿瘤T细胞活性 blocade-验证生物能量以在小鼠中灌输免疫力。 AIM 2将定义居民和淋巴记忆 供体T细胞保护小鼠免受转移的影响。研究还将测试Rexo2在皮肤中优先持续的REXO2如何 常驻供体T细胞会影响免疫学对自我抗衡肿瘤组织的影响。我们将使用人类和汽车T细胞 在癌症患者和与临床上与临床相关的异构人肿瘤小鼠模型中产生的产品 受到我们渴望深入研究具有直接翻译意义的研究的启发。即，这项工作提供了 基础数据以产生优化的，重定向的人T细胞，并具有较高的REXO2。这种方法是 有吸引力在功能较差的T细胞中增加免疫代谢并赋予它们介导耐用性的能力 对实体瘤的记忆反应。总体而言，拟议的研究非常重要，因为预计将表明 REXO2的操作可以安全防止肿瘤复发，而副作用减少了患者。