Abstract
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15–dependent homeostatic expansion and promoted the differentiation of memory precursor–like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
Highlights
The effector functions of T cells can be redirected against tumor antigens by gene transfer of T cell receptors (TCRs) or chimeric antigen receptors (CARs) to create large numbers of tumor-reactive cells for adoptive transfer
Upon entering the bone marrow (BM) sinusoids, TCXCR4 showed directed migration toward vascular-associated CXCL12+ cells and more efficiently competed for niches formed by IL-15 receptor α (IL-15Rα)+ cells
TCXCR4 adopted a less differentiated memory program characterized by resistance to apoptosis, low expression of programmed death-1 (PD-1), and polyfunctional cytokine secretion; collectively these properties translated into a greater capacity for expansion and improved per-cell functions
Summary
The effector functions of T cells can be redirected against tumor antigens by gene transfer of T cell receptors (TCRs) or chimeric antigen receptors (CARs) to create large numbers of tumor-reactive cells for adoptive transfer. Early-phase clinical trials of antitumor T cells have shown significant efficacy in certain tumors (e.g., the use of anti-CD19 CAR-T cells for the treatment of acute lymphoblastic leukemia), and several parameters have emerged that predict response; these include the number of cells infused, their replicative potential, and their in vivo persistence following transfer [1,2,3,4,5,6,7,8,9]. It has been shown that less differentiated T cells show greater in vivo expansion and survival than fully differentiated effector cells [12], a finding that relates to the former’s greater capacity for selfrenewal.
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