%0 Journal Article
%T Redirection to the bone marrow improves T cell persistence and antitumor functions
%A Angelika Holler
%A Anjum B. Khan
%A Barry Flutter
%A Ben Carpenter
%A Calum Forrest
%A Clare L. Bennett
%A Constina Pospori
%A Cristina Lo Celso
%A Emma Morris
%A Hans Stauss
%A James Griffin
%A Maryam Ahmadi
%A Mathias Zech
%A Pedro Santos e Sousa
%A Pedro Velica
%A Reema Khorshed
%A Ronjon Chakraverty
%A Sara Ghorashian
%A Sara Gonzalez Anton
%A Sharyn Thomas
%A Terry K. Means
%A Zaida Ramirez-Ortiz
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI97454
%X 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¨Cdependent homeostatic expansion and promoted the differentiation of memory precursor¨Clike 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
%U https://www.jci.org/articles/view/97454