Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy.

Apr 16, 2025Proceedings of the National Academy of Sciences of the United States of America

Creating stable versions of immune-signaling proteins CXCL9 and CXCL10 to improve cancer immunotherapy

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Abstract

(DPP-4) cleavage of CXCL9 and CXCL10 may limit their ability to activate the receptor.

CXCR3 is a receptor for the chemokines CXCL9, CXCL10, and CXCL11, which attract specific T cells and promote their activation.
The interaction between CXCL9/CXCL10 and CXCR3 may establish a self-amplifying cycle that enhances the effectiveness of cancer cell killing.
DPP-4 can cleave the N-terminal amino acids of CXCL9 and CXCL10, resulting in modified chemokines that bind to CXCR3 but do not activate it.
These modified chemokines become competitive antagonists, potentially limiting the efficacy of the CXCL9/10-CXCR3-IFNγ cycle.
A DPP-4-resistant variant of CXCL9 and CXCL10 was created, retaining their ability to activate CXCR3 while avoiding cleavage by DPP-4.
Preclinical evaluations suggest these variants may have significant therapeutic potential in cancer immunotherapy.

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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-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 (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. high

Key numbers

< 0.01

Increase in CD8+ T Cells

Compared to treatment

< 0.01

Tumor Growth Reduction

In C57BL/6 mice with MC38 colon cancer

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Abstract

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