The development of the efficacious anti-tumor DC therapies using TGF-beta antagonists

2018 Fiscal Year Annual Research Report

• Project/Area Number: 17K15735
• Research Institution: Tokyo Medical University
• Principal Investigator: 尹 晶煥 東京医科大学, 医学部, 兼任助教 (30748885)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: dendritic cell / TGF-β / Smad / differentiation / anti-tumor immunity

Outline of Annual Research Achievements

<Research Plan 1> The mechanisms how systemic TGF-β antagonists exert dose-dependent divergent effects on tumor immunity: In FY2017, I have found that the treatment with high-dose activin receptor-like kinase (ALK)5 inhibitor, EW7197 exacerbated the murine B16 melanoma model by rather accelerating the SMAD-mediated TGF-β signaling via blocking the negative feedback loop. In FY2018, I have found that complete ALK5 blockade by high-dose systemic TGF-β antagonists induced the paradoxical tumor-promoting effect via the selective modulation of TGF-β receptor-regulated Smads (R-Smads) in T cells.
<Research Plan 2> Molecular mechanisms how TGF-β regulates differentiation and maturation of dendritic cell (DC) subsets: In FY 2017, I have found that selective repression of one of the R-Smads is required for conventional DC (cDC), whereas it directs plasmacytoid DC (pDC) differentiation. In FY2018, I have clarified the mechanism how the R-Smad is repressed for cDC as well as the mechanism how it is maintained for pDC differentiation. Submitted manuscript has been under review and revision.
<Research Plan 3> Optimization of DC-based anti-tumor immunotherapies using TGF-β antagonists: In FY2017, I optimized the bone marrow-derived DC culture condition for adoptive DC therapy using the murine B16 melanoma model. In FY2018, I have found that ALK5 inhibitors distinctively modulate the expression patterns of R-Smads in BMDCs. I have found that the transfer of ALK5 inhibitor-treated BMDCs is efficacious against the murine B16 melanoma model. Manuscripts of 1 and 3 are in preparation.