Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity.
The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan. hiroakitan@med.osaka-cu.ac.jp
Hiroaki
H
Tanaka
Osamu
O
Shinto
Masakazu
M
Yashiro
Sadaaki
S
Yamazoe
Takehiko
T
Iwauchi
Kazuya
K
Muguruma
Naoshi
N
Kubo
Masaichi
M
Ohira
Kosei
K
Hirakawa
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004149:Dioxoles; D016212:Transforming Growth Factor beta