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posted on 2023-03-31, 20:23 authored by Tyler J. Wildes, Adam Grippin, Kyle A. Dyson, Brandon M. Wummer, David J. Damiani, Rebecca S. Abraham, Catherine T. Flores, Duane A. Mitchell T cell recognition of cognate antigen drives release of soluble factors including IFN-g and GM-CSF. T cell-released IFN-g and GM-CSF contribute to HSPC differentiation. Supernatant transfer with cytokine knockout T cells differentiates the roles of IFN-g and GM-CSF in HSPC differentiation and proliferation.
Funding
University of Florida
NCI
American Brain Tumor Association
Alex's Lemonade Stand Foundation
Florida Center for Brain Tumor Research
University of Florida, and University of Florida Clinical and Translational Science
History
ARTICLE ABSTRACT
Purpose: Adoptive T-cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively transferred tumor-reactive T cells and bone marrow–derived hematopoietic stem and progenitor cells (HSPCs) lead to the generation of potent intratumoral DCs within the CNS compartment.Experimental Design: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T-cell coculture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo. To demonstrate the impact of HSPC differentiation and function on antitumor efficacy, we performed survival experiments.Results: Transfer of HSPCs with concomitant ACT led to the production of activated CD86+CD11c+MHCII+ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T-cell–released IFNγ to differentiate into DCs, activate T cells, and reject intracranial tumors.Conclusions: Our data support the use of HSPCs as a novel cellular therapy. Although DC vaccines induce robust immune responses in the periphery, our data demonstrate that HSPC transfer uniquely generates intratumoral DCs that potentiate T-cell responses and promote glioma rejection in situ. Clin Cancer Res; 24(16); 3955–66. ©2018 AACR.
