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

Front Immunol. 2024 Oct 15:15:1452212. doi: 10.3389/fimmu.2024.1452212. eCollection 2024.

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.

Keywords: CXCL10; CXCL9; CXCR3; ICI; PD-1.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen* / metabolism
  • Cell Line, Tumor
  • Chemokine CXCL10* / genetics
  • Chemokine CXCL10* / metabolism
  • Chemokine CXCL9* / genetics
  • Chemokine CXCL9* / metabolism
  • Feedback, Physiological
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Interferon-gamma* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Programmed Cell Death 1 Receptor* / metabolism
  • Receptors, CXCR3* / genetics
  • Receptors, CXCR3* / metabolism

Substances

  • 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

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Grants from the DKFZ-MOST, the Israel Cancer Research Fund (ICRF), the Israel Science Foundation (ISF), the Israel Innovation Authority, and an academic research collaboration between Technion and Teva Pharmaceutical Industries, Ltd, supported this study.