Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

J Clin Invest. 2013 Oct;123(10):4410-22. doi: 10.1172/JCI69369. Epub 2013 Sep 9.


The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell-based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Animals
  • Bone Neoplasms / blood*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / secondary
  • Carcinoma / blood*
  • Carcinoma / immunology
  • Carcinoma / secondary
  • Cell Line, Tumor
  • Cell Proliferation
  • Histocompatibility Antigens Class I / blood*
  • Histocompatibility Antigens Class I / physiology
  • Homeostasis
  • Humans
  • Killer Cells, Natural / physiology*
  • Liver Neoplasms / blood*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary
  • Lung Neoplasms / blood*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Neoplasm Transplantation
  • Prostatic Neoplasms / blood*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology


  • Histocompatibility Antigens Class I
  • MICB antigen
  • NK Cell Lectin-Like Receptor Subfamily K