| First Author | Khan AB | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 5 | Pages | 2010-2024 |
| PubMed ID | 29485974 | Mgi Jnum | J:262860 |
| Mgi Id | MGI:6158742 | Doi | 10.1172/JCI97454 |
| Citation | Khan AB, et al. (2018) Redirection to the bone marrow improves T cell persistence and antitumor functions. J Clin Invest 128(5):2010-2024 |
| abstractText | 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. |
