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

肿瘤特异性 Th9 细胞在实体瘤根除中的独特作用

基本信息

批准号：
10706513
负责人：
Yong Lu
金额：
$ 38.88万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706513
关键词：
Adoptive Cell Transfers Adoptive Immunotherapy Antigen Targeting Antigens CD4 Positive T Lymphocytes Cancer Model Cells Clinical Clinical Trials Data Disease remission Dose Endogenous Retroviruses Endowment Ensure Enzymes Extracellular Matrix Foundations Future Genes Helper-Inducer T-Lymphocyte Heterogeneity Human Immune response Immunity Infiltration Interferon alpha Interleukin-9 Leukocytes MME gene Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Mus PPBP gene Patients Penetration Phenotype Production Recurrence Relapse Resistance Role Signal Transduction Solid Neoplasm T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TLR3 gene TRAF6 gene Therapeutic Index Tumor Antigens Work cancer cell chimeric antigen receptor effector T cell exhaust extracellular in vivo innovation melanoma monocyte mouse model neoplastic cell novel pre-clinical prevent proto-oncogene protein Spi-1 response restraint stem-like cell therapy resistant tumor tumor eradication tumor heterogeneity

项目摘要

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.

项目概要我们的早期研究将产生 IL-9 的 CD4+ T 辅助 (Th9) 细胞描述为抗肿瘤 T 细胞亚群。最近，我们还揭示了 Th9 细胞作为 ACT 的新型 T 细胞范例——它们不那么疲惫，完全溶细胞性和过度增殖性；并有效杀死目标抗原阳性肿瘤细胞。我们将使用忠实再现 ACT 在实体瘤中的临床情况的肿瘤模型来揭示肿瘤特异性 Th9 细胞的独特功能使其能够有效根除晚期实体瘤。认为 Th9 细胞的抗实体瘤活性主要归因于增强的 Th9 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复发肿瘤抗原表达的异质性将决定 Pu.1 依赖性 MMP12 产生的作用。 Th9 细胞有效渗透到实体瘤中发挥抗肿瘤功能将决定目标 2。 Th9 细胞在促进富含 eATP 的环境中的作用，以根除实体瘤中的 TANT 并预防我们提出的研究将确定肿瘤特异性 Th9 细胞作为第一个抗肿瘤 T 细胞。具有消除肿瘤抗原异质性实体瘤能力的子集这项与翻译相关的工作有望显着提高治疗指数。 ACT 在实体瘤中的应用可以为未来的临床试验奠定基础。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical drug screening reveals clofazimine potentiates the efficacy while reducing the toxicity of anti-PD-1 and CTLA-4 immunotherapy.

临床药物筛选显示氯法齐明可增强疗效，同时降低抗 PD-1 和 CTLA-4 免疫疗法的毒性。

DOI：
发表时间：
2024-03-19
期刊：
影响因子：
50.3
作者：
Xue, Gang;Li, Xin;Kalim, Muhammad;Fang, Jing;Jiang, Zhiwu;Zheng, Ningbo;Wang, Ziyu;Li, Xiaoyin;Abdelrahim, Maen;He, Zhiheng;Nikiforov, Mikhail;Jin, Guangxu;Lu, Yong
通讯作者：
Lu, Yong