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

• DOI: 10.3389/fimmu.2024.1452212
• Publication Date: 2024-10-15T08:56:57Z
• Authors: Noor Abdala-Saleh; Jennie Lugassy; Akshatha Shivakum...; Abeer Turky; Sari Abu Ras; Hila Razon; Nir Berger; Dana Bar-On; Yotam Bar-On; Tetsuya Taura; David Wilson; Nathan Karin
• Keywords: Mice, Knockout; Feedback, Physiological; CXCR3; ICI; Receptors, CXCR3; CXCL10; Immunology; Programmed Cell Death 1 Receptor; RC581-607; CD8-Positive T-Lymphocytes; Chemokine CXCL9; Chemokine CXCL10; Mice, Inbred C57BL; Mice; Interferon-gamma; CXCL9; Cell Line, Tumor; PD-1; Animals; Humans; CTLA-4 Antigen; Immunologic diseases. Allergy; Immune Checkpoint Inhibitors

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.