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

The Journal of Clinical Investigation
Anjum B KhanRonjon Chakraverty

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 ...Continue Reading

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Jul 5, 2018·Immunology·Felix Clemens RichterAnna Katharina Simon
Feb 2, 2019·European Journal of Immunology·Marieke GoedhartMartijn A Nolte
Jan 25, 2019·Current Stem Cell Research & Therapy·Marietta Herrmann, Franz Jakob
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Oct 6, 2020·Frontiers in Immunology·Francesco ManfrediEliana Ruggiero
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Aug 17, 2021·Frontiers in Cell and Developmental Biology·Shahrzad Jalali, Stephen M Ansell
Oct 29, 2021·The Journal of Experimental Medicine·Stephan IsringhausenCésar Nombela-Arrieta

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Methods Mentioned

BETA
transgenic
FACS
Assay
flow cytometry

Software Mentioned

GSEA
Definiens Developer
oligo
GraphPad Prism
GraphPad
Expression Console
BD
BioConductor R package
GenePattern
limma BioConductor R

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