A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

作者：Shono Yusuke; Tuckett Andrea Z; Ouk Samedy; Liou Hsiou Chi; Altan Bonnet Gregoire; Tsai Jennifer J; Oyler Jennifer E; Smith Odette M; West Mallory L; Singer Natalie V; Doubrovina Ekaterina; Pankov Dmitry; Undhad Chandresh V; Murphy George F; Lezcano Cecilia; Liu Chen; O'Reilly Richard J; van den Brink Marcel R M; Zakrzewski Johannes L^*

来源：Cancer Discovery, 2014, 4(5): 578-591.

DOI：10.1158/2159-8290.CD-13-0585

Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-kappa B family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen- specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.
SIGNIFICANCE: Chemical inhibition of c-Rel diminishes alloactivation while preserving antigen-specific TCR activation, revealing the redundancy of c-Rel in T cell-mediated antitumor activity of both mouse and human T cells. Our study provides a highly innovative immunomodulatory approach that has true potential for drug development and clinical application with broad therapeutic implications, including allo-tolerance induction after allo-HSCT, as well as antitumor therapies.

• 出版日期2014-5