A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity

TY - JOUR

T1 - A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity

AU - Shono, Yusuke

AU - Tuckett, Andrea Z.

AU - Ouk, Samedy

AU - Liou, Hsiou Chi

AU - Altan-Bonnet, Grégoire

AU - Tsai, Jennifer J.

AU - Oyler, Jennifer E.

AU - Smith, Odette M.

AU - West, Mallory L.

AU - Singer, Natalie V.

AU - Doubrovina, Ekaterina

AU - Pankov, Dmitry

AU - Undhad, Chandresh V.

AU - Murphy, George F.

AU - Lezcano, Cecilia

AU - Liu, Chen

AU - O'Reilly, Richard J.

AU - van den Brink, Marcel R.M.

AU - Zakrzewski, Johannes L.

PY - 2014/5

Y1 - 2014/5

N2 - 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-κB 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.

AB - 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-κB 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.

UR - https://www.scopus.com/pages/publications/84899699955

UR - https://www.scopus.com/pages/publications/84899699955#tab=citedBy

U2 - 10.1158/2159-8290.CD-13-0585

DO - 10.1158/2159-8290.CD-13-0585

M3 - Article

C2 - 24550032

SN - 2159-8274

VL - 4

SP - 578

EP - 591

JO - Cancer Discovery

JF - Cancer Discovery

IS - 5

ER -