Abstract
The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ-independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12- and TIM-3-mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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CD4 Lymphocyte Count
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Disease-Free Survival
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Gene Expression Regulation, Neoplastic / drug effects
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Hepatitis A Virus Cellular Receptor 2
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Humans
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Interferon-gamma / biosynthesis
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Interferon-gamma / pharmacology
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Interleukin-12 / biosynthesis
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Interleukin-12 / blood
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Interleukin-12 / pharmacology*
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Interleukin-12 / physiology
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Kaplan-Meier Estimate
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Lipopolysaccharides / pharmacology
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Lymphoma, Follicular / immunology
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Lymphoma, Follicular / metabolism
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Lymphoma, Follicular / mortality
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Lymphoma, Follicular / pathology*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Monocytes / drug effects
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Monocytes / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Prognosis
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Programmed Cell Death 1 Receptor / biosynthesis
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Programmed Cell Death 1 Receptor / genetics
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T-Lymphocyte Subsets / drug effects*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
Substances
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HAVCR2 protein, human
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Hepatitis A Virus Cellular Receptor 2
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Lipopolysaccharides
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Membrane Proteins
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Neoplasm Proteins
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Transcription Factors
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Interleukin-12
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Interferon-gamma