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01-11-2005 | Original Article

Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL-12 expression in macrophages

Authors: Hui Li, Ming Y. Cao, Yoon Lee, Vivian Lee, Ningping Feng, Tania Benatar, Hongnan Jin, Ming Wang, Sandy Der, Jim A. Wright, Aiping H. Young

Published in: Cancer Immunology, Immunotherapy | Issue 11/2005

Abstract

Virulizin, a novel biological response modifier, has demonstrated significant antitumor efficacy in a variety of human tumor xenograft models including melanoma, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer. The significant role of macrophages and NK (Natural killer) cells was implicated in the antitumor mechanism of Virulizin where expansion as well as increased activity of macrophages and NK cells were observed in mice treated with Virulizin. Depletion of macrophages compromised Virulizin-induced NK1.1⁺ cell infiltration into xenografted tumors and was accompanied by reduced antitumor efficacy. In the present study, involvement of macrophages in NK cell activation was investigated further. We found that depletion of NK cells in CD-1 nude mice by anti-ASGM1 antibody significantly compromised the antitumor activity of Virulizin. Cytotoxicity of NK cells isolated from Virulizin-treated mice was enhanced against NK-sensitive YAC-1 cells and C8161 human melanoma cells, but not against NK-insensitive P815 cells. An increased level of IL-12β was observed in the serum of mice treated with Virulizin. IL-12 mRNA and protein levels were also increased in peritoneal macrophages isolated from Virulizin-treated mice. Moreover, Virulizin-induced cytotoxic activity of NK cells isolated from the spleen was abolished when an IL-12 neutralizing antibody was co-administered. In addition, depletion of macrophages in mice significantly impaired Virulizin-induced NK cell cytotoxicty. Taken together, the results suggest that Virulizin induces macrophage IL-12 production, which in turn stimulates NK cell-mediated antitumor activity.

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Title: Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL-12 expression in macrophages
Authors: Hui Li
Ming Y. Cao
Yoon Lee
Vivian Lee
Ningping Feng
Tania Benatar
Hongnan Jin
Ming Wang
Sandy Der
Jim A. Wright
Aiping H. Young
Publication date: 01-11-2005
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 11/2005
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-005-0698-x

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