Novel mechanism of induction of tumor pyroptosis by IL-9-secreting Tc9 cells

分泌IL-9的Tc9细胞诱导肿瘤焦亡的新机制

• 批准号: 10704861
• 负责人: Qing Yi
• 金额: $ 47.32万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704861
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Antitumor Response; Apoptosis; Blood; CASP1 gene; CASP3 gene; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Clinical; Effector Cell; Foundations; Granzyme; Growth; Hallmark Cell; Human; IL18 gene; In Vitro; In complete remission; Induction of Apoptosis; Inflammatory; Interferons; Interleukin-2; Interleukin-9; Label; Longevity; Malignant Neoplasms; Mediating; PPBP gene; Patients; Play; Production; Role; STAT3 gene; Signal Transduction; Solid; T-Lymphocyte; TC1 Cell; Testing; Therapeutic; Translating; aged; antitumor effect; cancer immunotherapy; cancer therapy; cytokine; effector T cell; fitness; improved; in vivo; melanoma; neoplastic cell; novel; response; success; tumor; tumor microenvironment

PROJECT SUMMARY Blood CD8+ T cells can be subdivided into different subsets based on their cytokine section profiles and functions. We have shown that IL-9-secreting CD8+ Tc9 cells mediate a stronger antitumor effect in vivo compared to the classical IFN--secreting Tc1 or CTLs. However, the underlying mechanisms remain unclear. Recently, we discovered that Tc9 cells could eradicate large-established tumors by inducing an enhanced tumor pyroptosis, a form of programmed cell death dependent on caspase-1 activation. Our preliminary studies showed that Tc9 cell-treated tumors had increased expressions of IL-1 and IL-18 and activated caspase-1, and more tumor cell death compared to Tc1-treated tumors. Neutralizing IL-1 and IL-18 in vivo completely abrogated the therapeutic advantage of Tc9 cells over Tc1 cells in tumor controls. We further showed that tumor-specific Tc9 cells killed tumor cells by inducing both caspase-1-depedent pyroptosis and caspase-3- dependent apoptosis while Tc1 cells mainly induced apoptosis in tumor cells. Similarly, human tumor-specific Tc9 cells also displayed stronger antitumor effects in vivo compared to Tc1 cells, which was IL-1- and IL-18- dependent. Interestingly, we observed that IL-1 plus IL-18 induced apoptosis in cultured Tc1 but not Tc9 cells, Tc9 cell-derived IL-9 is critical for Tc9 cell activation of STAT3 and pro-growth and survival signaling and function, and IL-1 plus IL-18 can re-activate STAT3 and pro-growth and survival signaling in aged Tc9 cells with reduced IL-9 production. Thus, these findings reveal novel mechanisms underlying how Tc9 cells overcome the suppressive tumor microenvironment after transfer, survive and persist longer, and exert a greater antitumor activity as compared to the traditional Tc1 cells. We hypothesize that tumor-specific Tc9 subset may be superb effector T cells for cancer immunotherapy due to their capacity to induce both pyroptosis and apoptosis in tumor cells and utilize Tc9 cell-secreted IL-9 and tumor-produced IL-1 and IL-18 for their fitness, longevity, and function in vivo to effectively eradicate large established tumors. To test our hypothesis, Aim 1 will determine the importance and mechanisms of Tc9 cell-induced tumor cell pyroptosis in tumor clearance via IL-9- and GrzB-induced NFB-NLRP3-caspase-1-gasdermin activation, and Aim 2 will determine the role and mechanisms underlying Tc9 cell persistence and function mediated by Tc9 cell- secreted IL-9 and tumor-produced IL-1 and IL-18. Completing this project will reveal the importance and mechanism in induction of tumor pyroptosis by tumor-specific Tc9 cells and elucidate the mechanisms underlying the longevity and function of Tc9 cells in tumor microenvironment.

项目概要 血液 CD8+ T 细胞可根据细胞因子切片谱细分为不同的亚群 我们已经证明分泌 IL-9 的 CD8+ Tc9 细胞在体内介导更强的抗肿瘤作用。 与经典的 IFN-γ 分泌 Tc1 或 CTL 相比，但其潜在机制仍不清楚。 最近，我们发现 Tc9 细胞可以通过诱导增强的 肿瘤焦亡，一种依赖于 caspase-1 激活的程序性细胞死亡。 结果表明，Tc9 细胞处理的肿瘤 IL-1 和 IL-18 的表达增加，并激活了 caspase-1， 与 Tc1 处理的肿瘤相比，体内完全中和 IL-1 和 IL-18 的肿瘤细胞死亡更多。 在肿瘤对照中消除了 Tc9 细胞相对于 Tc1 细胞的治疗优势。 肿瘤特异性 Tc9 细胞通过诱导 caspase-1 依赖性细胞焦亡和 caspase-3- 杀死肿瘤细胞 类似地，Tc1细胞主要诱导肿瘤细胞凋亡，具有人类肿瘤特异性。 与Tc1细胞相比，Tc9细胞在体内也表现出更强的抗肿瘤作用，即IL-1-和IL-18- 依赖暗示，我们观察到 IL-1 加 IL-18 诱导培养的 Tc1 细胞凋亡，但不诱导 Tc9 细胞凋亡。 Tc9 细胞衍生的 IL-9 对于 Tc9 细胞激活 STAT3 以及促生长和存活信号传导至关重要 功能，IL-1 加 IL-18 可以重新激活老化 Tc9 细胞中的 STAT3 以及促生长和存活信号传导 因此，这些发现揭示了 Tc9 细胞如何产生的新机制。 克服转移后的抑制性肿瘤微环境，存活并持续更长时间，并发挥作用 与传统的 Tc1 细胞相比，我们捕获了肿瘤特异性 Tc9 更强的抗肿瘤活性。 子集可能是癌症免疫治疗的极好的效应 T 细胞，因为它们能够诱导 肿瘤细胞焦亡和凋亡，并利用 Tc9 细胞分泌的 IL-9 和肿瘤产生的 IL-1 和 IL-18 其适应性、寿命和体内功能可有效消除已形成的大型肿瘤。 假设，目标 1 将确定 Tc9 细胞诱导肿瘤细胞焦亡的重要性和机制 通过 IL-9 和 GrzB 诱导的 NF+B-NLRP3-caspase-1-gasdermin 激活来清除肿瘤，目标 2 将 确定 Tc9 细胞持久性和 Tc9 细胞介导的功能的作用和机制 分泌性 IL-9 和肿瘤产生的 IL-1 和 IL-18 的完成将揭示其重要性和意义。 肿瘤特异性Tc9细胞诱导肿瘤焦亡的机制并阐明其机制 Tc9 细胞在肿瘤微环境中的寿命和功能的基础。