Redirection to the bone marrow improves T cell persistence and antitumor functions
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
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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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 4

Ag-activated TCXCR4 adopt a less differentiated memory phenotype.

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Ag-activated TCXCR4 adopt a less differentiated memory phenotype. Equal ...
Equal numbers of OT-I TCXCR4 and TControl were coinjected into Rag1ko mice, which then underwent prime-boost vaccination with relevant SIINFEKL peptide plus IFA on days 1 and 29. Tissues were harvested on day 36 (n = 9); data are pooled from 4 independent experiments. (A and B) Representative flow cytometric histograms (A) and summary data (B) for expression of surface IL-15Rβ (CD122), intracellular Bcl2, EdU incorporation, and caspase-3 activity in TControl (blue) versus TCXCR4 (red) on day 36 in cells isolated from the BM. Statistical significance was tested using Wilcoxon’s ranked-sum test (2-tailed). *P ≤ 0.05, **P ≤ 0.01. (C and D) Representative flow cytometric histograms (C) and summary data (mean ± SD) (D) for CD62L and Bcl2 staining in BM TCXCR4 gated according to GFP reporter expression (gates 1–4).Numbers shown as insets of the flow cytometric histograms relate to CD62L median fluorescence index (MFI) and proportion of Bcl2+ cells in the gated subset. Statistical significance was tested using the Mann-Whitney test (2-tailed). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. (E and F) Representative flow cytometric contour plots (E) and summary data (F) for frequency of splenic TControl (blue) and TCXCR4 (red) with short-lived effector cell (SLEC) (KLRG-1hiCD127lo), MPEC (KLRG-1loCD127hi), and exhausted (PD-1hiEomeshi) phenotypes on day 36 (n = 5). Statistical significance was tested using Wilcoxon’s ranked-sum test (2-tailed). *P ≤ 0.05.