INTERLEUKIN-10 INHIBITS TUMOR-METASTASIS THROUGH AN NK CELL-DEPENDENTMECHANISM

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine se creted mainly by type 2 helper T cells. Previous studies have shown th at IL-10 suppresses cytokine expression by natural killer (NK) and typ e 1 T cells, thus down-regulating cell-mediated immunity and stimulati ng humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histo logical characterization after IL-10 treatment confirmed the absence o f CD8(+) and CD4(+) T cells and macrophages at the sites of tumor grow th, but abundant NK cells were localized at these sites. This unexpect ed finding was confirmed by showing that IL-10 inhibits most B16-F10 a nd Lox metastases in mice deficient in T or B cells (SCID) and nu/nu m ice), but not in those deficient in NK cells (beige mice or NK cell-de pleted mice). However, IL-10 downregulation of pro-inflammatory cytoki ne production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations o f IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumo r stage, and there was still a 33% inhibition of tumor metastasis in b eige mice.