Interleukin-10 Inhibits Tumor Metastasis, Downregulates MHC Class I, and Enhances NK Lysis

Abstract

We have engineered highly aggressive murine mammary tumor cell line 410.4 to express interleukin-10 (IL-10) and compared the behaviorin vivoof 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-γ reversed the class I downregulation and reduced the sensitivity of these cells to NK lysis. Taken together, these studiesin vitroandin vivoare 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.