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Redirection to the bone marrow improves T cell persistence and antitumor functions

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. Green open access

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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.

Type: Article
Title: Redirection to the bone marrow improves T cell persistence and antitumor functions
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI97454
Publisher version: http://doi.org/10.1172/JCI97454
Language: English
Additional information: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Cancer immunotherapy, Chemokines, Immunology, T cells, Therapeutics
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10045361
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