Redirection to the bone marrow improves T cell persistence and antitumor functions
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2018-05-01
Date Acceptance
2018-02-20
Citation
Journal of Clinical Investigation, 2018, 128 (5), pp.2010-2024
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
2010
End Page
2024
Journal / Book Title
Journal of Clinical Investigation
Volume
128
Issue
5
Copyright Statement
© 2018 Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000431959100028&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
MEMORY STEM-CELLS
SELF-RENEWAL
RECEPTOR
ACTIVATION
EFFICACY
CXCR4
FATE
RECRUITMENT
GENERATION
EXPRESSION
Publication Status
Published
Date Publish Online
2018-02-27