Abstract
Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / genetics
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Amino Acid Sequence
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Animals
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Clonal Anergy
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / genetics
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Imidazoles / pharmacology
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Imidazoles / therapeutic use*
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Immunotherapy / methods*
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Immunotherapy, Adoptive*
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics
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Interleukin-10 / metabolism*
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Interleukin-2 Receptor alpha Subunit / analysis
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Lymphocyte Depletion / methods*
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Lymphoma, Non-Hodgkin / immunology
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Lymphoma, Non-Hodgkin / therapy*
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Minor Lymphocyte Stimulatory Antigens / immunology
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Molecular Sequence Data
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / physiology
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Ovalbumin / immunology
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Peptide Fragments / immunology
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / immunology
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Superantigens / immunology
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T-Lymphocytes, Regulatory / drug effects*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Toll-Like Receptor 9 / biosynthesis
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Toll-Like Receptor 9 / genetics
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Tumor Escape / drug effects*
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Tumor Escape / immunology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Il2ra protein, mouse
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Imidazoles
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Interleukin-2 Receptor alpha Subunit
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Minor Lymphocyte Stimulatory Antigens
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Neoplasm Proteins
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OVA 323-339
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Peptide Fragments
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Pyridines
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Receptors, Antigen, T-Cell, alpha-beta
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Superantigens
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Tab1 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 9
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Interleukin-10
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Ovalbumin
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p38 Mitogen-Activated Protein Kinases
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SB 203580