| Title: |
Redirection to the bone marrow improves T cell persistence and antitumor functions |
| Authors: |
Khan, AB; Carpenter, B; Sousa, PSE; Pospori, C; Khorshed, R; Griffin, J; Veliça, 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 |
| Source: |
The Journal of Clinical Investigation , 128 (5) pp. 2010-2024. (2018) |
| Publication Year: |
2018 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Cancer immunotherapy; Chemokines; Immunology; T cells; Therapeutics |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10045361/7/De%20Ascensao%20Santos%20E%20Sousa_Anjum_B_Khan.pdf; https://discovery.ucl.ac.uk/id/eprint/10045361/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10045361/7/De%20Ascensao%20Santos%20E%20Sousa_Anjum_B_Khan.pdf; https://discovery.ucl.ac.uk/id/eprint/10045361/ |
| Rights: |
open |
| Accession Number: |
edsbas.BF98C810 |
| Database: |
BASE |