Genome-wide analysis of molecular changes in IL-12-induced control of mammary carcinoma via IFN-gamma-independent mechanisms.
IL-12 is a major activator of tumor-killing NK cells and CTL. IFN-gamma mediates most of the well-known immunological activities of IL-12. In this study, we report IFN-gamma-independent activities induced by therapeutic application of rIL-12 in restricting tumor growth and metastasis in the 4T1 murine mammary carcinoma model. IFN-gamma-deficient mice carrying 4T1 tumor exhibit no gross defect in the number of tumor-infiltrating lymphocytes but have exaggerated angiogenesis in the tumor. Administration of IL-12 is able to constrict blood vessels in the tumor in the absence of IFN-gamma, and retains certain therapeutic efficacy even when applied late during tumor progression. IL-12 exposure in vivo does not irreversibly alter the immunogenicity of the tumor. Finally, global gene expression analysis of primary tumors reveals IL-12-induced molecular patterns and changes, implicating a number of novel genes potentially important for IFN-gamma-independent immune responses against the tumor, for IL-12-mediated antiproliferation, antimetastasis, and antiangiogenesis activities.
Shi
Xiaoyan
X
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Cao
Shanjin
S
Mitsuhashi
Maki
M
Xiang
Zhaoying
Z
Ma
Xiaojing
X
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018925:Chemokines; D006131:Growth Inhibitors; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma