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

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Bibliographische Detailangaben
Zeitschriftentitel:	Cancer Discovery
Personen und Körperschaften:	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.
In:	Cancer Discovery, 4, 2014, 5, S. 578-591
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Oncology

Details
Zusammenfassung:	<jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:p>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. Cancer Discov; 4(5); 578–91. ©2014 AACR.</jats:p><jats:p>This article is highlighted in the In This Issue feature, p. 495</jats:p>
Umfang:	578-591
ISSN:	2159-8274 2159-8290
DOI:	10.1158/2159-8290.cd-13-0585