Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis.
We have engineered highly aggressive murine mammary tumor cell line 410.4 to express interleukin-10 (IL-10) and compared the behavior in vivo of these cells to parental 410.4 and 410.4 transfected with the control plasmid (410.4-neo). Transplantation of parental 410.4 and 410.4-neo tumor cells to syngeneic mice resulted in progressive growth and death from pulmonary metastases. In contrast, both subcutaneous growth and metastatic disease were completely inhibited by IL-10 expression. We had shown previously that the antimetastatic activity of IL-10 is expressed in T-cell-deficient mice but is lost when NK activity is suppressed. This study confirms that IL-10 is dependent on NK activity, since no therapeutic effect is seen in C.B-17/IcrCrl-SCID/Beige mice which lack T, B, and NK cell function. We compared the sensitivity to NK lysis of four IL-10-expressing clones with 410.4 and 410.4-neo and found that IL-10 expression resulted in enhanced NK lysis of all four clones. Furthermore, IL-10 expression was correlated with decreased surface expression of MHC class I Kd, Ld, and Dd. Pretreatment of IL-10-expressing cell lines with IFN-gamma reversed the class I downregulation and reduced the sensitivity of these cells to NK lysis. Taken together, these studies in vitro and in vivo are consistent with a mechanism by which IL-10 expression downregulates class I expression, leading to enhanced NK lysis of tumor cells, resulting in control of metastatic disease.
Kundu
N
N
Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore 21201, USA.
Fulton
A M
AM
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation
D015395:Histocompatibility Antigens Class I; D016753:Interleukin-10; D007371:Interferon-gamma