Abstract
With respect to CD8 effector T cells, interleukin-12 (IL-12) and transforming growth factor beta (TGFbeta) are 2 cytokines that exert opposing effects. IL-12 promotes antitumor immune responses by augmenting activated CD8 T-cell proliferation and interferon-gamma secretion. Conversely, TGFbeta generates a permissive environment for cancer growth, in part by antagonizing the effects of immunomodulatory cytokines, including IL-12. We demonstrate that TGFbeta-resistant T cells are capable of sustaining IL-12-induced mitogenesis and interferon-gamma secretion in a TGFbeta-rich milieu. Furthermore, in 2 murine tumor models associated with high TGFbeta1 levels in the local microenvironment, treatment with IL-12 and adoptively transferred TGFbeta-resistant T cells provided improved survival times. These results suggest that combining IL-12 with TGFbeta neutralization strategies may be effective in enhancing antitumor immune responses.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Cell Line
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Cell Proliferation
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Female
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Immunotherapy, Adoptive
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Interferon-gamma / biosynthesis
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Interleukin-12 / immunology
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Interleukin-12 / pharmacology*
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Male
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Melanoma, Experimental / mortality
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Melanoma, Experimental / pathology
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neoplasms, Experimental / mortality
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / therapy*
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Papilloma, Choroid Plexus / mortality
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Papilloma, Choroid Plexus / pathology
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Papilloma, Choroid Plexus / therapy
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Receptors, Transforming Growth Factor beta / genetics
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T-Lymphocytes / immunology
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T-Lymphocytes / transplantation*
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Transforming Growth Factor beta1 / immunology*
Substances
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Interleukin-12
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Interferon-gamma