Khan, AB;
Carpenter, B;
Sousa, PSE;
Pospori, C;
Khorshed, R;
Griffin, J;
Veliça, P;
... Chakraverty, R; + view all
(2018)
Redirection to the bone marrow improves T cell persistence and antitumor functions.
The Journal of Clinical Investigation
, 128
(5)
pp. 2010-2024.
10.1172/JCI97454.
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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 re-directing T cells to specialized niches in the bone marrow (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 towards 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 poly-functional 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, re-directed homing of T cells to the BM confers increased memory differentiation and anti-tumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
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