Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1

J Immunol. 2009 Jan 1;182(1):240-9. doi: 10.4049/jimmunol.182.1.240.


NK cells, the important effector of innate immunity, play critical roles in the antitumor immunity. Myeloid-derived suppressor cells (MDSC), a population of CD11b(+)Gr-1(+) myeloid cells expanded dramatically during tumor progression, can inhibit T cells and dendritic cells, contributing to tumor immune escape. However, regulation of NK cell innate function by MDSC in tumor-bearing host needs to be investigated. In this study, we found that the function of NK cells from liver and spleen was impaired significantly in all tumor-bearing models, indicating the impairment of hepatic NK cell function by tumor is a universal phenomenon. Then we prepared the orthotopic liver cancer-bearing mice as tumor model to investigate how hepatic NK cells are impaired. We show that down-regulation of NK cell function is inversely correlated with the marked increase of MDSC in liver and spleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. After incubation with MDSC, NK cells could not be activated to produce IFN-gamma. Furthermore, membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-beta1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host. Our study provides new mechanistic explanations for tumor immune escape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Clonal Anergy / immunology*
  • Coculture Techniques
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms, Experimental / immunology*
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / immunology*
  • Myeloid Cells / pathology
  • Myeloid Cells / transplantation
  • Neoplasm Transplantation
  • Protein Binding / immunology
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / physiology*
  • Tumor Escape / immunology


  • Membrane Proteins
  • Transforming Growth Factor beta1