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

Redirection to the bone marrow improves T cell persistence and antitumor functions.
Author Information (click to view)

Khan AB, Carpenter B, Santos E Sousa P, Pospori C, Khorshed R, Griffin J, Velica P, Zech M, Ghorashian S, Forrest C, Thomas S, Gonzalez Anton S, Ahmadi M, Holler A, Flutter B, Ramirez-Ortiz Z, Means TK, Bennett CL, Stauss H, Morris E, Lo Celso C, Chakraverty R,


Khan AB, Carpenter B, Santos E Sousa P, Pospori C, Khorshed R, Griffin J, Velica P, Zech M, Ghorashian S, Forrest C, Thomas S, Gonzalez Anton S, Ahmadi M, Holler A, Flutter B, Ramirez-Ortiz Z, Means TK, Bennett CL, Stauss H, Morris E, Lo Celso C, Chakraverty R, (click to view)

Khan AB, Carpenter B, Santos E Sousa P, Pospori C, Khorshed R, Griffin J, Velica P, Zech M, Ghorashian S, Forrest C, Thomas S, Gonzalez Anton S, Ahmadi M, Holler A, Flutter B, Ramirez-Ortiz Z, Means TK, Bennett CL, Stauss H, Morris E, Lo Celso C, Chakraverty R,

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The Journal of clinical investigation 2018 04 09() doi 10.1172/JCI97454

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 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-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, 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.

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