Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms.

Abstract

The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4MyeΔ/Δ) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4MyeΔ/Δ mice exhibited slowed tumor progression compared with CXCR4WT mice in an inducible melanocyte BrafV600E/Pten -/- mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4MyeΔ/Δ mice as compared with myeloid cells from CXCR4WT mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4MyeΔ/Δ mice. NK cells from CXCR4MyeΔ/Δ mice also exhibited increased tumor cell killing capacity in vivo, based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4MyeΔ/Δ neutrophils. Furthermore, enhanced NK cell activity in CXCR4MyeΔ/Δ mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4WT mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. Cancer Immunol Res; 6(10); 1186-98. ©2018 AACR.

• Authors: Jinming Yang, Amrendra Kumar, Anna E Vilgelm, Sheau-Chiann Chen, Gregory D Ayers, Sergey V Novitskiy, Sebastian Joyce, Ann Richmond
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 6 Issue 10 Pg. 1186-1198 (10 2018) ISSN: 2326-6074 [Electronic] United States
• PMID: 30108045 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• CXCR4 protein, human
• Fas Ligand Protein
• Interleukin-18
• Receptors, CXCR4

Topics

• Animals
• Bone Marrow Transplantation
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Fas Ligand Protein (immunology)
• Interleukin-18 (immunology)
• Killer Cells, Natural (immunology)
• Macrophages (immunology)
• Melanoma, Experimental (immunology, therapy)
• Mice, Inbred C57BL
• Mice, Transgenic
• Neutrophils (immunology)
• Receptors, CXCR4 (antagonists & inhibitors, genetics, immunology)