Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer

Shaorong Deng; Qing Deng; Yingjie Zhang; Hao Ye; Xiaolan Yu; Yang Zhang; Grace Yq Han; Ping Luo; Mingyuan Wu; Yan Yu; Wei Han

doi:10.1016/j.canlet.2018.11.017

Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer

Cancer Lett. 2019 Feb 28:443:1-12. doi: 10.1016/j.canlet.2018.11.017. Epub 2018 Nov 24.

Authors

Shaorong Deng¹, Qing Deng², Yingjie Zhang¹, Hao Ye¹, Xiaolan Yu², Yang Zhang², Grace Yq Han³, Ping Luo¹, Mingyuan Wu¹, Yan Yu⁴, Wei Han⁵

Affiliations

¹ Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China.
² Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, PR China.
³ College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA.
⁴ Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address: yanyu@sjtu.edu.cn.
⁵ Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address: weihan@sjtu.edu.cn.

PMID: 30481563
DOI: 10.1016/j.canlet.2018.11.017

Abstract

CXCL4 is mainly produced by activated platelets, and certain somatic cells and cancer cells also express CXCL4. However, the physiological function of non-platelet-derived CXCL4 is unclear. Previously, we reported that CXCL4 produced by cancer cells accelerated tumor growth by suppressing the antitumor activities of cytotoxic T lymphocytes (CTLs). To elucidate the mechanism of CXCL4 in tumor immunity, we compared the CTLs and regulatory T cells (Tregs) from CXCL4^-/-, CXCR3^-/- and C57BL/6 mice overexpressing CXCL4 via intramuscular electroporation. CXCL4 accelerated tumor growth in CXCL4^-/- and C57BL/6 mice but not in CXCR3^-/- mice. Furthermore, CXCL4 decreased CTLs proliferation and IFN-γ production and enhanced CTLs apoptosis and programmed death 1 (PD-1) expression. Conversely, CXCL4 promoted Tregs proliferation and TGF-β production and downregulated PD-1 expression in Tregs. Notably, these effects of CXCL4 were both observed in the splenic and tumor-infiltrating CTLs and Tregs from wild-type but not CXCR3^-/- mice. Thus, we revealed a negative immune regulatory function for non-platelet-derived CXCL4 through CXCR3 that cancer cells could hijack to evade the host immune system, suggesting that the CXCL4/CXCR3 axis may serve as a novel target for colorectal cancer immunotherapy.

Keywords: CXCL4; CXCR3; Cancer immunology; Cancer immunotherapy; Colorectal cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Colonic Neoplasms / genetics
Colonic Neoplasms / immunology
Colonic Neoplasms / pathology*
Humans
Interferon-gamma / metabolism
Lymphocytes, Tumor-Infiltrating / immunology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Transplantation
Platelet Factor 4 / genetics*
Programmed Cell Death 1 Receptor / metabolism
Receptors, CXCR3 / genetics*
Spleen / immunology
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Regulatory / immunology*

Substances

CXCR3 protein, human
IFNG protein, human
PDCD1 protein, human
PF4 protein, human
Programmed Cell Death 1 Receptor
Receptors, CXCR3
Platelet Factor 4
Interferon-gamma