Gene expression analysis in Interleukin‐12‐induced suppression of mouse mammary carcinoma

Abstract

Interleukin-12 (IL-12) has potent antitumor activities via natural killer cells and cytotoxic T lymphocytes. However, the molecular mechanisms whereby IL-12 induces tumoricidal activities are poorly understood. Here, we report the genome-wide analysis of gene expression in a primary murine mammary carcinoma model that resembles human breast cancer, following the therapeutic application of recombinant IL-12, which restricted tumor growth and metastasis. IL-12 was able to curtail neovascularization in the tumor as well as enhance the number of tumor-infiltrating lymphocytes. Comprehensive examination of global gene expression revealed IL-12-induced molecular changes associated with tumor regression and reduced lung metastasis, thus providing a high-resolution snapshot of a host response against a developing malignancy and a rich source of potential targets for therapeutic intervention of breast cancer. © 2004 Wiley-Liss, Inc. mammary carcinoma; metastasis; angiogenesis Tumors often possess a number of potential recognition sites for immunologic effector cells, which, in theory, could make them susceptible to immune surveillance. Nevertheless, most of such tumors grow progressively in their natural hosts or syngeneic recipients, without being controlled effectively by the immune system. The lack of apparent immunogenicity of tumors in situ might be due to special properties of the tumor cells, e.g., lack of costimulatory molecules, downregulation of MHC molecules, or production of immunosuppressive factors 1,2 or due to intrinsic tolerance mechanisms of the immune system. 3 Two principal types of cells are immunologically potent tumor-killing effectors: NK and CTL. A major activator of both cell types is Interleukin-12 (IL-12). NK cells kill tumors by intrinsic and nonspecific mechanisms hinged on a lack of MHC molecules on the surface of the tumor. CTL, on the other hand, recognizes specific antigenic peptides that are derived from the tumor and presented to them by antigen-presenting cells such as dendritic cells (DCs). In recent years, immunotherapy has been rekindled that attempts to either mark the tumor by upregulating the surface antigens for enhanced interaction with immune effector cells 2,4 or by directly activating DC, T and NK cells for their heightened "scouting" capacity and increased cytolytic potency. IL-12 is a factor belonging to the latter class. 5 IL-12 has powerful anti-tumor and anti-metastatic activities against many murine tumors as well as human tumors. 6 Recent encouraging developments in clinical applications of IL-12 for human T cell lymphoma, 7,8 B cell non-Hodgkin lymphoma, 9 melanoma 10 -14 and renal carcinoma 15 and SIV-infection model in rhesus macaques 16 strongly underscore the importance of understanding the cellular and molecular mechanisms of IL-12me-diated anti-tumor responses. The potent anti-malignancy activities of IL-12 are thought to be mediated through similar mechanisms that are used by IL-12 against infectious agents, i.e., via the activation of NK cells for the bu...

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New insights into IL-12-mediated tumor suppression

“…administration of IL-12 also induced effective antitumor immune responses against malignant glioma 60 and 4T1 mammary carcinoma. 61 Apart from direct effects on primary tumors, IL-12 was also able to eradicate lung metastasis when mammary tumors were surgically removed. 61 The potent antitumor activity exerted by IL-12 made it an ideal candidate for combination with other therapy modalities directed to increase the immunogenicity of the tumor.…”

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