Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer

Abstract

Background: Interleukin 10 (IL-10) is a potent immunoregulatory cytokine. It inhibits some cell functions, including T-helper (Th1) cell activity (i.e., interleukin 2 and interferon gamma production), and stimulates other functions such as a natural killer (NK) activity. In mice, IL-10 suppresses tumorigenicity in a xenograft system using a nonmetastasizing hamster cell line.

Purpose: We evaluated the antitumor and antimetastatic properties of IL-10 in syngeneic immunocompetent and immunocompromised murine hosts.

Methods: Using the plasmids pBMGneo and pBMGneo.IL-10, we transfected the highly malignant murine mammary tumor cell lines 410.4 and 66.1 (transfectants designated as 410.4-IL10 and 66.1-IL10, 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 w ere measured in immunocompetent, syngeneic BALB/cByJ mice as well as in immunocompromised C.B-17/IcrCrl-SCID/Beige mice.

Results: Tumor growth was completely inhibited following inoculations of 5 x 10(6)410.4-IL10 cells in immunocompetent, syngeneic BALB/cByJ mice. This inoculum contains 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 and transplantation. The tumorigenicity of 66.1-IL-10, compared with that of its parent cell line, was also significantly abrogated by IL-10 expression. Furthermore, in immunocompetent mice, the metastatic potential of both 410.4-IL10 and 66.1-IL10 was also completely inhibited. In immunocompromised C.B-17/IcrCrl-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 cells. In spite of the more limited efficacy of IL-10 against tumor growth in immunocompromised mice, spontaneous metastasis of 410.4-IL10 cells in C.B-17/IcrCrl-SCID/BR mice was inhibited by 90%. When NK activity was suppressed by asialoGM1 ganglioside antibody in BALB/cByJ mice or 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 immunocompromised hosts. This effect thus appears to be relatively independent of T-cell function but is dependent on NK activity. In contrast, the inhibitory effect of IL-10 on tumorigenicity relies on T-cell function.

Implications: Based on the recent observation of others that IL-10 has little toxicity when administered systemically to human volunteers and also on the findings of this study that it has antitumor and antimetastitic properties in mice, possible use of IL-10 in the treatment of human metastatic cancers deserves consideration.