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

• Published in: Cancer discovery Vol. 4; no. 5; p. 578
• Main Authors: Shono, Yusuke, Tuckett, Andrea Z, Ouk, Samedy, Liou, Hsiou-Chi, Altan-Bonnet, Grégoire, 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
• Format: Journal Article
• Language: English
• Published: United States 01-05-2014
• Subjects: Animals; Female; Gene Expression Regulation; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Graft vs Tumor Effect - immunology; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proto-Oncogene Proteins c-rel - antagonists & inhibitors; Proto-Oncogene Proteins c-rel - genetics; Proto-Oncogene Proteins c-rel - metabolism; Receptors, Antigen, T-Cell - metabolism; Small Molecule Libraries - pharmacology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transplantation, Homologous
• ISSN: 2159-8290
• 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-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.