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| Home > Institute Collections > W500 > Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy. |
| Home > Institute Collections > W500 > Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy. |
| Journal Article | DKFZ-2025-02686 |
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2025
National Acad. of Sciences
Washington, DC
Abstract: CXCR3 is a chemokine receptor for three ligands: CXCL9, CXCL10, and CXCL11. Accumulating evidence, including data presented here, suggests that the interaction between CXCL9/CXCL10 and CXCR3 not only attracts CXCR3+ T cells but also promotes the induction of IFNγ-high effector/cytotoxic CD4+ and CD8+ T cells, establishing a CXCL9/10-CXCR3-IFNγ self-amplifying cycle that promotes efficient cancer cell killing. One of the homeostatic mechanisms that may limit this cycle is the cleavage of the two N-terminal amino acids of these chemokines by Dipeptidyl Peptidase IV (DPP-4). The modified chemokines retain their ability to bind CXCR3 but no longer activate it, becoming competitive antagonists to native CXCL9/CXCL10. To develop a DPP-4-resistant variant, we combined biochemical analysis with computational modeling, demonstrating that the addition of N-terminal glutamine (Q) to CXCL9-Fc and CXCL10-Fc rendered them fully active CXCR3 agonists, yet resistant to DPP-4 cleavage. Preclinical evaluations imply that they offer significant therapeutic potential in cancer immunotherapy.
Keyword(s): Chemokine CXCL9: genetics (MeSH) ; Chemokine CXCL9: metabolism (MeSH) ; Chemokine CXCL9: immunology (MeSH) ; Chemokine CXCL9: chemistry (MeSH) ; Chemokine CXCL10: genetics (MeSH) ; Chemokine CXCL10: metabolism (MeSH) ; Chemokine CXCL10: immunology (MeSH) ; Chemokine CXCL10: chemistry (MeSH) ; Dipeptidyl Peptidase 4: metabolism (MeSH) ; Dipeptidyl Peptidase 4: genetics (MeSH) ; Receptors, CXCR3: metabolism (MeSH) ; Receptors, CXCR3: immunology (MeSH) ; Humans (MeSH) ; Immunotherapy: methods (MeSH) ; Neoplasms: therapy (MeSH) ; Neoplasms: immunology (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Immunoglobulin Fc Fragments: genetics (MeSH) ; Immunoglobulin Fc Fragments: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; CXCL10 ; CXCR3 ; DPP-4 ; T cell subsets ; immunotherapy ; Chemokine CXCL9 ; Chemokine CXCL10 ; Dipeptidyl Peptidase 4 ; Receptors, CXCR3 ; CXCR3 protein, human ; CXCL9 protein, human ; CXCL10 protein, human ; Immunoglobulin Fc Fragments ; DPP4 protein, human
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