ANTIMETASTATIC AND ANTITUMOR ACTIVITIES OF INTERLEUKIN-10 IN A MURINEMODEL OF BREAST-CANCER

Background: Interleukin 10 (IL-10) is a potent immunoregulatory cytoki ne. It inhibits some cell functions, including T-helper (Th1) cell act ivity (i.e., interleukin 2 and interferon gamma production), and stimu lates other functions such as natural killer (NK) activity. In mice, I L-10 suppresses tumorigenicity in a xenograft system using a nonmetast asizing hamster cell line. Purpose: We evaluated the antitumor and ant imetastatic properties of IL-10 in syngeneic immunocompetent and immun ocompromised murine hosts. Methods: Using the plasmids pBMGneo and pBM Gneo, IL-10, we transfected the highly malignant murine mammary tumor cell lines 410.4 and 66.1 (transfectants designated as 410.4-IL.10 and 66.1-IL.10, respectively) to stably express IL-10 (2-100 U IL-10/2.5 x 10(5) cells per 48 hours). Tumorigenic and metastatic activities of the parent and transfected cells were measured in immunocompetent, syn geneic BALB/cByJ mice as well as in immunocompromised C.B-17/IcrCrl-SC ID/BR and C.B-17/IcrCrl-SCID/Beige mice. Results: Tumor growth was com pletely inhibited following inoculation of 5 x 10(6) 410.4-IL.10 cells in immunocompetent, syngeneic BALB/cByJ mice. This inoculum contained 100 times the minimum cell number required for 100% tumor incidence. In contrast, tumor growth following the inoculation of parental 410.4 or 410.4-neo cells was progressive, resulting in death of animals from pulmonary metastases at days 40-50 after transplantation. The tumorig enicity of 66.1-IL.10, compared with that of its parent cell line, was also significantly abrogated by IL-10 expression. Furthermore, in imm unocompetent mice, the metastatic potential of both 410.4-IL.10 and 66 .1-IL10 was also completely inhibited. In immunocompromised C.B-17/Icr Crl-SCID/BR or C.B-17/IcrCrl-SCID/Beige mice, subcutaneous implants of 410.4-IL10 grew progressively, but growth was inhibited significantly in comparison to that produced by the parental 410.4 or 410.4-neo cel ls. In spite of the more limited efficacy of IL-10 against tumor growt h in immunocompromised mice, spontaneous metastasis of 410.4-IL.10 cel ls in C.B-17/IcrCrl-SCID/BR mice was inhibited by 90%. When NK activit y was suppressed by asialoGM1 ganglioside antibody in BALB/cByJ mice o r in C.B-17/IcrCrl-SCID/Beige mice, the antimetastatic effect of IL-10 was lost. Conclusions: These data show for the first time that IL-10 is a potent antimetastatic agent that is effective in immunocompromise d hosts. This effect thus appears to be relatively independent of T-ce ll function but is dependent on NK activity. In contrast, the inhibito ry effect of IL-10 on tumorigenicity relies on T-cell function. Implic ations: Based on the recent observation of others that IL-10 has littl e toxicity when administered systemically to human volunteers and also on the findings of this study that it has antitumor and antimetastati c properties in mice, possible use of IL-10 in the treatment of human metastatic cancers deserves consideration.