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| Home > Institute Collections > W500 > PD-1 and CTLA-4 serve as major gatekeepers for effector and cytotoxic T-cell potentiation by limiting a CXCL9/10-CXCR3-IFNγ positive feedback loop. |
| Home > Institute Collections > W500 > PD-1 and CTLA-4 serve as major gatekeepers for effector and cytotoxic T-cell potentiation by limiting a CXCL9/10-CXCR3-IFNγ positive feedback loop. |
| Journal Article | DKFZ-2025-02462 |
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2024
Frontiers Media
Lausanne
Abstract: CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy. Results from a panel of in vivo and ex vivo 3D tumor models imply that, beyond driving CD8+ T cells into T-cell exhaustion, a major role of PD-1 and CTLA-4 is in limiting the CXCR3-based self-feeding mechanism of T cell potentiation. This may explain why patients that are CXCL9/CXCL10high tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10low. It also suggests a therapeutic role for CXCL9-Fc or CXCL10-Fc therapy; herein we demonstrate significant anti-tumor activity in multiple murine tumor models with such agents.
Keyword(s): Animals (MeSH) ; Receptors, CXCR3: metabolism (MeSH) ; Receptors, CXCR3: genetics (MeSH) ; Chemokine CXCL9: metabolism (MeSH) ; Chemokine CXCL9: genetics (MeSH) ; Mice (MeSH) ; Chemokine CXCL10: metabolism (MeSH) ; Chemokine CXCL10: genetics (MeSH) ; Programmed Cell Death 1 Receptor: metabolism (MeSH) ; CTLA-4 Antigen: metabolism (MeSH) ; Interferon-gamma: metabolism (MeSH) ; Mice, Knockout (MeSH) ; Mice, Inbred C57BL (MeSH) ; Feedback, Physiological (MeSH) ; Humans (MeSH) ; Cell Line, Tumor (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; CXCL10 ; CXCL9 ; CXCR3 ; ICI ; PD-1 ; Receptors, CXCR3 ; Chemokine CXCL9 ; Chemokine CXCL10 ; Programmed Cell Death 1 Receptor ; CTLA-4 Antigen ; Interferon-gamma ; Cxcl9 protein, mouse ; Pdcd1 protein, mouse ; Cxcr3 protein, mouse ; Cxcl10 protein, mouse ; Ctla4 protein, mouse ; Immune Checkpoint Inhibitors
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