Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Adoptive T cell transfer (ACT) therapy mediates potent immunity in some patients with aggressive malignancies, but many individuals do not respond or relapse. One reason for therapy failure is due to lack of T cell persistence. To overcome this problem, we aimed to generate a cell product that will lead to long term immunity to aggressively growing tumors. Our team reported that antigen-specific CD4+ T cells that secrete IL-17, termed Th17 cells, persist long term and can eradicate large solid tumors when infused into mice. We found that in the tumor and draining lymph node of mice treated with Th17 therapy, there was a vast induction of genes in the MHC-II pathway as well as key cytokines, costimulatory cues, and transcription factors known to support B cell differentiation and maturation. Furthermore, host B cells were surprisingly critical in sustaining durable immunity, as their depletion impaired survival. In mice deficient in B cells, IL-21 and IFN-g production by Th17 cells was impaired. Importantly, our findings show for the first time an active role for B cells in ACT. Based on our findings, we propose the central hypothesis that IL-21 and IFN-g enhance Th17 and B cell cooperativity, in turn sustaining long lived responses via MHC-II dependent pathways and tumor specific antibodies. To test this hypothesis, in Aim 1, we will examine how IL-21 and IFN-g support Th17-B cell cooperation. Th17 cells, deficient or sufficient in IL-21R or IFN-gR, will be infused into melanoma-bearing mice, with or without IL-21R, or IFN- gR, and we will test how IL-21 and IFN- g signaling governs Th17 and B cell self-renewal, proliferation, maturation, and networking. In Aim 2, we will determine how transferred Th17 cells synergize with host B cells to mediate tumor immunity. To address this, we will determine if Th17 cells can directly kill tumor in an MHC-II restricted manner by performing in vitro killing assays with Th17 cells against melanoma (with or without MHC-II expression). Further, Th17 cells will be transferred into mice, deficient or sufficient in MHC-II expressing B cells, bearing melanoma (with or without MHC-II expression) to test the idea that both MHC-II on tumor and B cells is needed for sustained immunity. Additionally, we will test if the antibodies induced by Th17 cell therapy are tumor specific. To test this, we will transfer antibodies from Th17 cured mice into treatment naïve mice challenged with lung metastasis to test if these antibodies can protect tumor formation. These investigations are expected to expose the mechanism behind Th17 and B cell antitumor cooperativity in turn informing the development of novel therapies to bolster immunity against aggressive tumors that evade current treatments.
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