Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 5, Pages 2010-2024Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI97454
Keywords
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Categories
Funding
- Medical Research Council [G0802345]
- Wellcome Trust [201049/Z/16/Z]
- Fundacao para a Ciencia e a Tecnologia [SFRH/BD/76516/2011]
- Biotechnology and Biological Sciences Research Council [BB/L023776/1]
- European Research Council [337066]
- [13057]
- [15040]
- European Research Council (ERC) [337066] Funding Source: European Research Council (ERC)
- Wellcome Trust [201049/Z/16/Z] Funding Source: Wellcome Trust
- BBSRC [BB/L023776/1] Funding Source: UKRI
- MRC [G0701703, G0802345] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L023776/1] Funding Source: researchfish
- Cancer Research UK [11831] Funding Source: researchfish
- Medical Research Council [G0802345] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20265] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/76516/2011] Funding Source: FCT
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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 (T-CXCR4) enhanced their migration toward vascular-associated CXCL12(+) cells in the BM and increased their local engraftment. Increased access of T-CXCR4 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, T-CXCR4 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.
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