TY  - JOUR
AU  - Lugassy, Jennie
AU  - Abdala-Saleh, Noor
AU  - Jarrous, Ghada
AU  - Turky, Abeer
AU  - Saidemberg, Daniel
AU  - Ridner-Bahar, Gabriela
AU  - Berger, Nir
AU  - Bar-On, Dana
AU  - Taura, Tetsuya
AU  - Wilson, David
AU  - Karin, Nathan
TI  - Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 122
IS  - 16
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2025-02686
SP  - e2501791122
PY  - 2025
N1  - #DKFZ-MOST-Ca188#
AB  - 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.
KW  - Chemokine CXCL9: genetics
KW  - Chemokine CXCL9: metabolism
KW  - Chemokine CXCL9: immunology
KW  - Chemokine CXCL9: chemistry
KW  - Chemokine CXCL10: genetics
KW  - Chemokine CXCL10: metabolism
KW  - Chemokine CXCL10: immunology
KW  - Chemokine CXCL10: chemistry
KW  - Dipeptidyl Peptidase 4: metabolism
KW  - Dipeptidyl Peptidase 4: genetics
KW  - Receptors, CXCR3: metabolism
KW  - Receptors, CXCR3: immunology
KW  - Humans
KW  - Immunotherapy: methods
KW  - Neoplasms: therapy
KW  - Neoplasms: immunology
KW  - Animals
KW  - Mice
KW  - Immunoglobulin Fc Fragments: genetics
KW  - Immunoglobulin Fc Fragments: immunology
KW  - Cell Line, Tumor
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - CXCL10 (Other)
KW  - CXCR3 (Other)
KW  - DPP-4 (Other)
KW  - T cell subsets (Other)
KW  - immunotherapy (Other)
KW  - Chemokine CXCL9 (NLM Chemicals)
KW  - Chemokine CXCL10 (NLM Chemicals)
KW  - Dipeptidyl Peptidase 4 (NLM Chemicals)
KW  - Receptors, CXCR3 (NLM Chemicals)
KW  - CXCR3 protein, human (NLM Chemicals)
KW  - CXCL9 protein, human (NLM Chemicals)
KW  - CXCL10 protein, human (NLM Chemicals)
KW  - Immunoglobulin Fc Fragments (NLM Chemicals)
KW  - DPP4 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40238455
C2  - pmc:PMC12037015
DO  - DOI:10.1073/pnas.2501791122
UR  - https://inrepo02.dkfz.de/record/306696
ER  -