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

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.