Redirection to the bone marrow improves T cell persistence and antitumor functions
Anjum B. Khan, … , Cristina Lo Celso, Ronjon Chakraverty
Anjum B. Khan, … , Cristina Lo Celso, Ronjon Chakraverty
Published February 27, 2018
Citation Information: J Clin Invest. 2018;128(5):2010-2024. https://doi.org/10.1172/JCI97454.
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Research Article Immunology

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

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.

Authors

Anjum B. Khan, Ben Carpenter, Pedro Santos e Sousa, Constandina Pospori, Reema Khorshed, James Griffin, Pedro Velica, Mathias Zech, Sara Ghorashian, Calum Forrest, Sharyn Thomas, Sara Gonzalez Anton, Maryam Ahmadi, Angelika Holler, Barry Flutter, Zaida Ramirez-Ortiz, Terry K. Means, Clare L. Bennett, Hans Stauss, Emma Morris, Cristina Lo Celso, Ronjon Chakraverty

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Figure 1

Adoptively transferred TCXCR4 demonstrate superior recruitment to the BM.

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Adoptively transferred TCXCR4 demonstrate superior recruitment to the BM...
(A) Representative flow cytometry plots for CXCR4 expression in untreated CD8+ T cells (unstimulated), TControl, or TCXCR4. Gating based on “fluorescence minus 1” controls. CXCR4 median fluorescence index (MFI): 380 unstimulated; 587 GFP+ TControl; 2,409 GFP+ TCXCR4. (B and C) Equal mixtures of TCXCR4 (CD45.1+) and TControl (Thy1.1+) were injected into sublethally irradiated B6 mice. Representative plots of TCXCR4 (red) and TControl (blue) frequencies in BM, spleen (Sp), and LN at day 7 are shown in B. Summary graphs in C indicate mean ± SD TCXCR4/TControl ratio at timed intervals in BM, Sp, and LN (n = 6 per group at 3 and 24 hours, n = 4 per group at day 7). Statistical comparison was performed by Wilcoxon’s signed-rank test against a hypothetical ratio of 1.0 (dotted line). *P ≤ 0.05. (D) Box-and-whisker graphs for BM/LN ratio on day 14 following transfer of TCXCR4 or TControl to separate sublethally irradiated B6 mice, calculated by division of percent GFP+ of BM CD8+ T cells by percent GFP+ of LN CD8+ T cells (n = 6 TCXCR4, n = 5 TControl). (E) Box-and-whisker graphs of TCXCR4/TControl ratio in BM, Sp, and LN at day 7 following transfer into sublethally irradiated B6 mice (n = 4) and untreated Rag1ko mice (n = 10). (F) Box-and-whisker graphs of TCXCR4/TControl ratio in BM, Sp, and LN at day 7 following transfer into untreated B6 mice (n = 11) and untreated Rag1ko mice (n = 10). (G) Box-and-whisker graphs of ratio of TCXCR4/TControl in BM, Sp, and LN at day 7 following transfer into Rag1ko (n = 10), Rag1ko.Il15rako (n = 10), and Rag1ko.Il7ko (n = 4). Statistical comparisons in D and E were made using the Mann-Whitney test (2-tailed). *P ≤ 0.05, **P ≤ 0.01. All data are pooled from 2–3 independent experiments.