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effect; stem; stemness; transcriptome sequencing; translational impact; tumor; tumor eradication; tumor metabolism; unpublished works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细胞的代谢特性可以影响它们对实体瘤产生有效反应的能力。 这种限制与最佳过继性细胞治疗方法特别相关，其中肿瘤抗原 向患者施用靶向T细胞以根除肿瘤。我们的团队已经取得了很大的进步， 通过我们发现用CAL-101选择性阻断PI 3 K p110δ亚型， （Idealisib®）在体外可以重新连接T细胞的代谢，并使它们在体内施用后有效地与T细胞结合。 荷瘤小鼠。重要的是，这些T细胞的耐久性与其增强的线粒体功能有关。 生物能量学和持久性，以及对肿瘤复发进行快速回忆反应的非凡能力， 挑战.虽然小鼠从这种疗法中治愈，但它们经常发展为自身免疫性白癜风。我们的最新数据 揭示了虽然PI 3 K δ抑制性T细胞在体外具有干细胞特性，但它们成为组织驻留细胞， 淋巴组织中的效应记忆细胞。这些挑衅性的结果意味着，他们可能会合作， 凭借其记忆表型在宿主范围内保护免受转移，并在动物中引发白癜风。我们 在这些有效的PI 3 K δ抑制T细胞上进行了RNAseq，并鉴定了一种新的寡核糖核酸酶，称为 REXO 2。我们的初步数据表明，基因切除REXO 2消除了他们对抗肿瘤的能力，但 过表达REXO 2支持线粒体生物发生、抗肿瘤代谢，并赋予T细胞 作为过继细胞疗法的功效。这些创新的数据是第一个定义REXO 2作为一种 增强ACT的可行因素。这项提案将揭示支持T细胞代谢的机制， 在REXO 2和PI 3 K信号传导的背景下的免疫力，并促进ACT的未来翻译工作， REXO 2操纵的人类T细胞。我们假设REXO 2支持抗肿瘤T细胞的代谢， REXO 2可以在T细胞中发挥作用，以提高ACT的疗效。REXO 2在T细胞中的作用及其机制 治疗潜力将在三个互补的具体目标进行研究：AIM 1将确定机制 PI 3 K δ靶向支持抗肿瘤T细胞活性，通过研究REXO 2如何通过PI 3 K δ- 封锁支持生物能量学，以向小鼠灌输免疫力。AIM 2将定义常驻记忆和淋巴记忆 供体T细胞保护小鼠免受转移。研究还将测试REXO 2如何优先在皮肤中维持- 常驻供体T细胞，影响对自身与肿瘤组织的免疫力。我们将使用人TIL和CAR T细胞 在癌症患者和临床相关异种人肿瘤小鼠模型中产生的产物， 我们渴望深入研究具有直接翻译意义的研究。也就是说，这项工作提供 基础数据，以产生优化的，重定向的人T细胞与升高的REXO 2。这种方法 有吸引力的是增强功能低下的T细胞的免疫代谢，并使它们能够介导持久的免疫应答。 对实体瘤的记忆反应总的来说，拟议的研究是重要的，因为它预计将揭示， REXO 2的操作可以安全地防止肿瘤复发，同时减少对患者的副作用。