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.

项目总结 血液CD8+T细胞可根据其细胞因子切片图谱和 功能。我们已经证明分泌IL-9的CD8+Tc9细胞在体内介导了更强的抗肿瘤作用 与经典的分泌干扰素-的Tc1或CTL相比较。然而，潜在的机制仍不清楚。 最近，我们发现Tc9细胞可以通过诱导增强的 肿瘤下垂，一种依赖于caspase-1激活的程序性细胞死亡。我们的初步研究 结果表明，经Tc9细胞处理的肿瘤组织中IL-1和IL-18表达增加，caspase-1活化， 与Tc1治疗的肿瘤相比，肿瘤细胞死亡更多。体内完全中和IL-1和IL-18 在肿瘤对照中，Tc9细胞相对于Tc1细胞的治疗优势被取消。我们进一步表明， 肿瘤特异性Tc9细胞通过诱导caspase-1依赖性下垂和caspase-3-2共同杀伤肿瘤细胞. 依赖于细胞凋亡，而Tc1细胞主要诱导肿瘤细胞的凋亡。同样，人类肿瘤特异性 与Tc1细胞相比，Tc9细胞在体内的抗肿瘤作用也更强，即IL-1-和IL-18- 依附的。有趣的是，我们观察到IL-1联合IL-18诱导培养的Tc1细胞凋亡，但不诱导Tc9细胞的凋亡。 TC9细胞来源的IL-9对TC9细胞激活STAT3、促生长和生存信号至关重要，并 IL-1联合IL-18可重新激活STAT3、促生长和存活信号 IL-9的产生减少。因此，这些发现揭示了Tc9细胞潜在的新机制 克服移植后抑制性肿瘤微环境，存活和存活时间更长，发挥更大的作用 与传统的Tc1细胞相比具有更强的抗肿瘤活性。我们假设肿瘤特异性Tc9 亚群可能是用于癌症免疫治疗的超级效应T细胞，因为它们能够诱导两者 肿瘤细胞趋化与凋亡及利用Tc9细胞分泌的IL-9和肿瘤产生的IL-1和IL-18 因为它们的适合性、寿命和在体内有效根除大的已建立的肿瘤的功能。测试我们的 假设，目标1将确定Tc9细胞诱导的肿瘤细胞恶性下垂的重要性和机制 IL-9和GrzB诱导的NFB-NLRP3-Caspase-1-Gasdermin激活清除肿瘤，AIM 2将 确定Tc9细胞介导的Tc9细胞持久性和功能的作用和机制 分泌IL-9和肿瘤产生的IL-1和IL-18。完成这个项目将揭示出 肿瘤特异性Tc9细胞诱导肿瘤下垂的机制及机制探讨 Tc9细胞在肿瘤微环境中的寿命和功能。