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Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis
Gang Liu, … , Zihai Li, Jennifer D. Wu
Gang Liu, … , Zihai Li, Jennifer D. Wu
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4410-4422. https://doi.org/10.1172/JCI69369.
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Research Article Oncology

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

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Abstract

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.

Authors

Gang Liu, Shengjun Lu, Xuanjun Wang, Stephanie T. Page, Celestia S. Higano, Stephen R. Plymate, Norman M. Greenberg, Shaoli Sun, Zihai Li, Jennifer D. Wu

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Figure 3

Prostate carcinoma progression is associated with sMICB-induced impairment in NK cell peripheral maintenance.

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Prostate carcinoma progression is associated with sMICB-induced impairme...
(A and B) Comparisons of splenic CD8 (A) and NK (B) cells and NKG2D+ population in cohorts of 24-week-old TRAMP/MICB, TRAMP, and wild-type B6 mice. Left panel, representative dot plots of flow cytometry analyses. Right panel, pooled statistical data of flow cytometry analyses of each cohort. **P < 0.001 in comparison with TRAMP mice or with TRAMP/MICB mice that developed WD tumors. (C) Significant inverse correlation of serum sMICB with splenic NK cell population as analyzed from the cohort of 24-week-old TRAMP/MICB mice. (D) Representative dot plots of flow cytometry analyses and statistics of pooled data demonstrating systemic (LN, BM, and blood) depletion of NK cells in TRAMP/MICB mice that developed PD carcinoma. (E) Representative dot plots of flow cytometry analyses and statistical data demonstrating significant reduction of NK cells in tumor infiltrated lymphocytes (TILs) in PD tumors from TRAMP/MICB mice. All data show represents results from 3 independent assays of at least 5 animals.
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