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

项目摘要 我们早期的研究表明，产生IL-9的CD4+T辅助细胞(Th9)是一种抗肿瘤T细胞亚群。 最近，我们还发现Th9细胞是ACT的一种新的T细胞范例--它们不那么疲惫，完全 具有溶细胞性和高增殖性；并能有效杀死靶抗原阳性的肿瘤细胞。在当前的项目中， 我们将使用肿瘤模型，忠实地概括ACT在实体肿瘤中的临床情景，以揭示 肿瘤特异性Th9细胞的独特功能，使它们能够有效地根除晚期实体肿瘤。我们 假设Th9细胞的抗实体瘤活性主要归因于增强的Th9细胞 穿透富含间质的实体瘤，抑制因获得性耐药引起的复发 肿瘤抗原表达的异质性。目标1将确定依赖于PU1的MMP12产生的作用 在Th9细胞中以其高效的穿透实体瘤发挥抗肿瘤功能。目标2将决定 Th9细胞在促进eATP富集型环境中清除实体瘤中的细菌和预防 后天抵抗力。我们提出的研究将确定肿瘤特异性Th9细胞是第一个抗肿瘤T细胞 具有消除肿瘤抗原异质性的实体瘤能力的亚集 表情。这项与翻译相关的工作有望显著提高糖尿病的治疗指数 对实体肿瘤起作用，然后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.