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

• Published in: Frontiers in immunology 2024-10, Vol.15, p.1452212
• Main Authors: Abdala-Saleh, Noor, Lugassy, Jennie, Shivakumar-Kalvhati, Akshatha, Turky, Abeer, Abu Ras, Sari, Razon, Hila, Berger, Nir, Bar-On, Dana, Bar-On, Yotam, Taura, Tetsuya, Wilson, David, Karin, Nathan
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Chemokine CXCL10 - genetics; Chemokine CXCL10 - metabolism; Chemokine CXCL9 - genetics; Chemokine CXCL9 - metabolism; CTLA-4 Antigen - metabolism; CXCL10; CXCL9; CXCR3; Feedback, Physiological; Humans; ICI; Immune Checkpoint Inhibitors - pharmacology; Immunology; Interferon-gamma - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; PD-1; Programmed Cell Death 1 Receptor - metabolism; Receptors, CXCR3 - genetics; Receptors, CXCR3 - metabolism
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1452212

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 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/CXCL10 tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10 . 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.