Tumor growth impedes natural-killer-cell maturation in the bone marrow.
Natural-killer (NK)-cell dysfunction and IFN-gamma deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, breast cancer, colon cancer, and melanoma cell lines, interrupt functional maturation during NK-cell development in the bone marrow. The immature NK cells in the periphery of tumor-bearing mice had impaired IFN-gamma production but seemingly normal cytotoxicity. T cells are not involved in this NK maturation arrest, because T-cell depletion did not restore NK-cell development. Moreover, the extent of tumor-cell infiltration into the bone marrow does not correlate with defective NK maturation. Interestingly, the defect was associated with a significant reduction in the IL-15Ralpha+ cells in the non-T, non-NK compartment of bone marrow cells and restored by overexpression of IL-15. Our data demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway.
Division of Cancer Immunology, Department of Pathology, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.
John O
JO
Richards
Xing
X
Chang
Bradley W
BW
Blaser
Michael A
MA
Caligiuri
Pan
P
Zheng
Yang
Y
Liu
D000818:Animals; D001853:Bone Marrow / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D019409:Interleukin-15; D007371:Interferon-gamma