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J Hematol Oncol. 2015 Feb 20;8:13. doi: 10.1186/s13045-015-0110-z.

Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype.

Xiao G1,2, Wang X3, Sheng J4, Lu S5,6, Yu X7,8, Wu JD9,10.

Author information

1
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. xiaog@musc.edu.
2
Present address: The Third Hospital of South Medical University, Guangzhou, China. xiaog@musc.edu.
3
Key Lab for Puer Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China. wangxuanjun@gmail.com.
4
Key Lab for Puer Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China.
5
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. lussh@musc.edu.
6
Present Address: Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. lussh@musc.edu.
7
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. yux@musc.edu.
8
Cancer Immunology Program, Hollings Cancer Center, Charleston, SC, USA. yux@musc.edu.
9
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. wujjd@musc.edu.
10
Cancer Immunology Program, Hollings Cancer Center, Charleston, SC, USA. wujjd@musc.edu.

Abstract

Expression of surface NKG2D ligand MIC on tumor cells is deemed to stimulate NK and co-stimulate CD8 T cell anti-tumor immunity. Human cancer cells however frequently adopt a proteinase-mediated shedding strategy to generate soluble MIC (sMIC) to circumvent host immunity. High levels of sMIC have been shown to correlate with advanced disease stages in cancer patients. The underlying mechanism is currently understood as systemic downregulation of NKG2D expression on CD8 T and NK cells and perturbing NK cell periphery maintenance. Herein we report a novel mechanism by which sMIC poses immune suppressive effect on host immunity and tumor microenvironment. We demonstrate that sMIC facilitates expansion of myeloid-derived suppressor cells (MDSCs) and skews macrophages to the more immune suppressive alternative phenotype through activation of STAT3. These findings further endorse that sMIC is an important therapeutic target for cancer immunotherapy.

PMID:
25887583
PMCID:
PMC4342005
DOI:
10.1186/s13045-015-0110-z
[Indexed for MEDLINE]
Free PMC Article

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