© 1996 by Oxford University Press
Journal of the National Cancer Institute, Vol. 88, No. 8, 536-541,
April 17, 1996
© 1996 Oxford University Press
Antimetastatic and Antitumor Activities of Interleukin 10 in a Murine Model of Breast Cancer
Department of Pathology and the University of Maryland Cancer Center Baltimore
Medical Biotechnology Center and Department of Neurology, University of Maryland School of Medicine Baltimore
Correspondence to: Amy M. Fulton, Ph.D., Department of Pathology, University of Maryland Cancer Center, 10 S. Pine St., Baltimore, MD 21201.
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 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 105 cells per 48 hours). Tumorigenic and metastatic activities of the parent and transfected cells were measured in immunocompetent, syngeneic BALB/cByJ mice as well as in immunocompromised C.B-17/IcrCrl-SCID/BR and C.B-17/IcrCrl-SCID/Beige mice.
RESULTS:: Tumor growth was completely inhibited following inoculation of 5 x 106 410.4-IL10 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 tumorigenicity of 66.1-IL10, 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 antimetastatic properties in mice, possible use of IL-10 in the treatment of human metastatic cancers deserves consideration. [J Natl Cancer Inst 1996;88:536–41]
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