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 Therapeutics

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 3

Ag-activated TCXCR4 retain a CD62Lhi phenotype.

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Ag-activated TCXCR4 retain a CD62Lhi phenotype. Equal numbers of OT-I TC...
Equal numbers of OT-I TCXCR4 and TControl were coinjected into Rag1ko mice, before prime-boost vaccination with relevant SIINFEKL peptide plus IFA (Antigen, n = 17) or irrelevant peptide plus IFA (No antigen, n = 8) on days 1 and 29. Tissues were harvested on day 8 (n = 4 per group), 29 (n = 3 Ag, n = 1 no Ag), and 36 (n = 9 Ag, n = 3 no Ag). Data from 4 independent experiments (with the exception of day 29 no-Ag group derived from 1 experiment). (A) Summary (mean ± SD) TCXCR4/TControl in BM, Sp, and LN over time for no-Ag (circles, dashed lines) and Ag groups (squares, solid line). Arrows indicate time of prime-boost vaccination. (B) Summary (mean ± SD) CD62L expression over time in TCXCR4 (red) and TControl (blue) in no-Ag (left) and Ag groups (right). (C) Representative plots for TCXCR4 and TControl accumulation and surface expression of CD44 and CD62L on day 36 in BM, Sp, and LN. Numbers denote frequencies of TCXCR4 (red), TControl (blue), and proportions of CD62Lhi and CD62Llo cells (black). (D) Box-and-whisker graphs showing summary of TCXCR4/TControl ratios in BM, Sp, and LN on day 36 following transfer into Rag1ko (Il15ra WT, n = 9) and Rag1ko.Il15rako (Il15rako, n = 6) mice undergoing the same prime-boost vaccination schedule outlined in A. Data derived from 3 independent experiments. (E) Box-and-whisker graphs showing summary data for CD62L expression by TControl or TCXCR4 on day 36 in the same experiments outlined in D. In A and D, statistical comparisons were made by Wilcoxon’s signed-rank test against a hypothetical ratio of 1.0 (dotted line). *P ≤ 0.05, **P ≤ 0.01. In B, C, and E, statistical comparisons were made using the Mann-Whitney test (2-tailed). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.