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Published online before print April 23, 2004

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(Journal of Leukocyte Biology. 2004;76:338-351.)
© 2004 by Society for Leukocyte Biology

Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells

Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women’s College Health Sciences Center, Toronto, Canada; Toronto-Sunnybrook Regional Cancer Center, Canada; and Departments of Medicine and Medical Biophysics, University of Toronto, Canada

¹Correspondence: Division of Molecular and Cellular Biology, Research Institute, S-116A, Research Building, Sunnybrook and Women’s College Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. E-mail: spanerd{at}srcl.sunnybrook.utoronto.ca

Immunosuppressive factors, such as vascular endothelial growth factor, transforming growth factor-ß, prostaglandin E₂, interleukin (IL)-10, and IL-6, are made frequently by cancer cells. These factors, along with others, can inhibit the development and function of tumor-reactive effector T cells and the clinical results of cancer vaccines. Production of these factors by tumor cells is associated with disease progression and may represent an active immune surveillance escape mechanism. However, a number of factors appear to be made directly in response to signaling molecules, such as RAS, AKT, and signal transducer and activator of transcription 3, which are activated as a result of genetic events that occur during oncogenesis. Methods to overcome the negative effects of immunosuppressive factors, which are "hard wired" into gene programs of cancer cells, might then improve the results of cancer vaccines. For example, specific blocking antibodies, which recognize such factors, or kinase inhibitors, which block the signaling pathways that lead to their production, could potentially be used as vaccine adjuvants. The effects of immunosuppressive factors may also be "turned off" by cytokines with tumor suppressor properties. The enhanced clinical and immunological effects of melanoma vaccines observed after the administration of high doses of interferon-2b provide a "proof of principle" in human patients, that agents which counter the gene programs of cancer cells, causing them to intrinsically resist tumor-reactive T cells, may improve significantly the efficacy of cancer vaccines.

Key Words: human • tumor immunity • cytokines • signal transduction

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