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Expression of the CXCR4 S338X variant improves anti-leukemia efficacy of anti-CD19 CAR-T cells

ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable success in treating hematological malignancies; however, antigen-positive relapse remains a significant obstacle to achieving sustained remission in B-cell acute lymphoblastic leukemia (B-ALL). To enhance the therapeutic efficacy of anti-CD19 CAR (CAR19)-T cells, we overexpressed CXCR4 in CAR19-T cells to improve their trafficking to bone marrow (BM), a key sanctuary for minimal residual disease. We engineered CAR19-T cells with overexpression of wild-type CXCR4 (CAR19/CXCR4WT-T) or gain-of-function CXCR4 S338X mutant (CAR19/CXCR4S338X-T). Both CAR19/CXCR4WT-T and CAR19/CXCR4S338X-T cells exhibited enhanced CXCR4 surface expression in vitro and in vivo compared to control CAR19-T cells, with the latter showing significantly superior improvements under all tested conditions, including engagement with CAR-specific antigens or CXCR4 ligand CXCL12. Upon engagement with CXCL12, CAR19/CXCR4S338X-T cells, but not CAR19/CXCR4WT-T cells, displayed significantly increased activation of ERK1/2 and AKT signaling pathways, as well as elevated transcription of TNF-α, IFN-γ, granzyme B, CDK6, and BCL2A1, along with strengthened effector functions, chemotaxis, and activation of anti-apoptotic pathways. Furthermore, CAR19/CXCR4S338X-T cells demonstrated significantly improved migration to and retention in the BM accompanied by increased CD45RA+CCR7+ memory T cell populations, which correlated with enhanced anti-leukemic effects following injection into B-ALL-bearing mice. This study offers a potentially effective strategy to improve the functionality and durability of CAR-T cell responses in hematological malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314992 | GEO | 2025/12/28

REPOSITORIES: GEO

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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Expression of the CXCR4 S338X variant improves anti-leukemia efficacy of anti-CD19 CAR-T cells

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