INTERLEUKIN-10 INHIBITS TUMOR-METASTASIS, DOWN-REGULATES MHC CLASS-I,AND ENHANCES NK LYSIS

We have engineered highly aggressive murine mammary tumor cell line 41 0.4 to express interleukin-10 (IL-10) and compared the behavior in viv o of these cells to parental 410.4 and 410.4 transfected with the cont rol plasmid (410.4-neo). Transplantation of parental 410.4 and 410.4-n eo tumor cells to syngeneic mice resulted in progressive growth and de ath from pulmonary metastases. In contrast, both subcutaneous growth a nd metastatic disease were completely inhibited by IL-10 expression. W e had shown previously that the antimetastatic activity of IL-10 is ex pressed in T-cell-deficient mice but is lost when NK activity is suppr essed. This study confirms that IL-10 is dependent on NK activity, sin ce no therapeutic effect is seen in C.B-17/lcrCrl-SCID/Beige mice whic h lack T, B, and NK cell function. We compared the sensitivity to NK l ysis of four IL-10-expressing clones with 410.4 and 410.4-neo and foun d that IL-10 expression resulted in enhanced NR lysis of all four clon es. Furthermore, IL-10 expression was correlated with decreased surfac e expression of MHC class I K-d, L-d, and D-d. Pretreatment of IL-10-e xpressing cell lines with IFN-gamma reversed the class I downregulatio n and reduced the sensitivity of these cells to NK lysis. Taken togeth er, these studies in vitro and in vivo are consistent with a mechanism by which IL-10 expression downregulates class I expression, leading t o enhanced NK lysis of tumor cells, resulting in control of metastatic disease. (C) 1997 Academic Press.