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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.

项目总结