The Unique Roles of Tumor-Specific Th9 Cells for Solid Tumor Eradication

项目摘要 我们的早期研究已经将产生IL-9的CD 4 + T辅助细胞（Th 9）表征为抗肿瘤T细胞亚群。 最近，我们还揭示了Th 9细胞作为ACT的一种新的T细胞范例-它们不那么疲惫，完全 细胞溶解和过度增殖;并有效杀死靶向抗原阳性肿瘤细胞。在目前的项目中， 我们将使用真实再现ACT在实体瘤中的临床情况的肿瘤模型， 肿瘤特异性Th 9细胞的独特功能使其能够有效根除晚期实体瘤。我们 假设Th 9细胞抗实体瘤活性主要归因于增强的Th 9细胞 渗透到富含基质的实体瘤中，并抑制由于高耐药性而导致的获得性耐药性引起的复发。 肿瘤抗原表达的异质性。目的1将确定Pu.1依赖性MMP 12产生的作用 在Th 9细胞中，它们有效地渗透到实体瘤中以发挥抗肿瘤功能。目标2将决定 Th 9细胞在促进eATP富集的环境中消除实体瘤中的TANTs并预防肿瘤发生中的作用 获得性抵抗我们提出的研究将确定肿瘤特异性Th 9细胞作为第一个抗肿瘤T细胞 具有消除具有肿瘤抗原异质性的实体瘤的能力的亚群 表情这项与临床相关的工作有望显著提高 ACT在实体瘤中的应用，可以为未来的临床试验奠定基础。

Project Summary Our early studies have characterized IL-9-producing CD4+ T helper (Th9) cells as an antitumor T cell subset. Recently, we also revealed Th9 cells as a novel T cell paradigm for ACT – they are less exhausted, fully cytolytic, and hyperproliferative; and efficiently kills targeted antigen-positive tumor cells. In the current project, we will use tumor models that faithfully recapitulate the clinical scenario of ACT in solid tumors, to uncover unique features of tumor-specific Th9 cells that enable them to efficiently eradicate advanced solid tumors. We hypothesize that anti-solid tumor activity of Th9 cells are mainly attributed to both enhanced Th9 cell penetration into stroma-rich solid tumors and restrain relapse caused by acquired resistance due to high heterogeneity in tumor antigen expression. Aim 1 will determine the role of Pu.1-dependent MMP12 production in Th9 cells for their efficient penetration into solid tumors to exert antitumor functions. Aim 2 will determine the role of Th9 cells in promoting an eATP-enriched milieu to eradicate the TANTs in solid tumors and prevent acquired resistance. Our proposed studies will identify tumor-specific Th9 cells as the first antitumor T cell subset that are endowed with the capacity to eliminate solid tumors with the heterogeneity in tumor antigen expression. This translationally relevant work holds promise to significantly advance the therapeutic index of ACT in solid tumors and could then lay the foundation for future clinical trials.