Targeted inhibition of IL-10-secreting CD25- Treg via p38 MAPK suppression in cancer immunotherapy.
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.
Ohkusu-Tsukada
Kozo
K
Department of Veterinary Pathology, Nippon Veterinary and Life-science University (NVLU), Tokyo, Japan. tkd-oks@nvlu.ac.jp
Toda
Masahiro
M
Udono
Heiichiro
H
Kawakami
Yutaka
Y
Takahashi
Kimimasa
K
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017635:Clonal Anergy; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008212:Lymphocyte Depletion / Q000379:methods*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics; D019139:Tumor Escape / Q000187:drug effects* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007093:Imidazoles; D053645:Interleukin-2 Receptor alpha Subunit; D016747:Minor Lymphocyte Stimulatory Antigens; D009363:Neoplasm Proteins; C111390:OVA 323-339; D010446:Peptide Fragments; D011725:Pyridines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C531463:Tab1 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D010047:Ovalbumin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580