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Publication Detail
Redirection to the bone marrow improves T cell persistence and antitumor functions
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Khan AB, Carpenter B, Sousa PSE, Pospori C, Khorshed R, Griffin J, Veli├ža P, Zech M, Ghorashian S, Forrest C, Thomas S, Anton SG, Ahmadi M, Holler A, Flutter B, Ramirez-Ortiz Z, Means TK, Bennett CL, Stauss H, Morris E, Celso CL, Chakraverty R
  • Publication date:
    27/02/2018
  • Journal:
    The Journal of clinical investigation
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Print ISSN:
    0021-9738
  • Language:
    eng
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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Research Department of Haematology
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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