Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade.

Abstract

PURPOSE:

Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies.

EXPERIMENTAL DESIGN:

The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoString-based analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses.

RESULTS:

The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8+ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8+ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB.

CONCLUSIONS:

These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.

• Authors: Imran G House, Peter Savas, Junyun Lai, Amanda X Y Chen, Amanda J Oliver, Zhi L Teo, Kirsten L Todd, Melissa A Henderson, Lauren Giuffrida, Emma V Petley, Kevin Sek, Sherly Mardiana, Tuba N Gide, Camelia Quek, Richard A Scolyer, Georgina V Long, James S Wilmott, Sherene Loi, Phillip K Darcy, Paul A Beavis
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 2 Pg. 487-504 (01 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31636098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• CXCL10 protein, human
• CXCL9 protein, human
• CXCR3 protein, human
• Chemokine CXCL10
• Chemokine CXCL9
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, CXCR3

Topics

• Animals
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• CTLA-4 Antigen (antagonists & inhibitors)
• Cell Line, Tumor
• Chemokine CXCL10 (metabolism)
• Chemokine CXCL9 (metabolism)
• Immunotherapy (methods)
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Neoplasms (drug therapy, immunology, metabolism, pathology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Receptors, CXCR3 (metabolism)
• Tumor Microenvironment