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 5

Ag-activated TCXCR4 have increased potential for polyfunctional cytokine generation.

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Ag-activated TCXCR4 have increased potential for polyfunctional cytokine...
Equal numbers of OT-I TCXCR4 and OT-I TControl were coinjected into Rag1ko mice, which then underwent prime-boost vaccination with relevant SIINFEKL peptide plus IFA on days 1 and 29. T cells were isolated from the spleen on day 36 (n = 7). (A) Representative flow cytometric contour plots showing IFN-γ and TNF-α intracellular costaining in OT-I TCXCR4 and OT-I TControl after ex vivo stimulation with relevant peptide with gates set according to stimulation with irrelevant peptide. (B) Summary data for IFN-γ, TNF-α, and IL-2 generation from OT-I TControl (blue) and OT-I TCXCR4 (red) in the same assays. Statistical significance tested using the Wilcoxon ranked sum test (two-tailed), *P ≤ 0.05, **P ≤ 0.01. (C) Pie charts depicting polyfunctional cytokine generation in TControl and TCXCR4 according to Boolean combination gates identifying IFN-γ+, TNF‑α+, and IL-2+ cells. (D) Transduced OT-I TCXCR4 and OT-I TControl were stimulated in vitro with relevant or irrelevant peptide and in the absence or presence of 500 ng/ml of recombinant murine CXCL12. Representative flow cytometric contour plots showing CD44 and CD62L surface expression. Data shown are representative of 2 independent experiments. (E) Summary data (mean ± SD) for intracellular IFN-γ generation after in vitro stimulation with anti-CD3 in the presence or absence of CXCL12 (n = 3 from 3 independent experiments).