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

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)578-591
Number of pages14
JournalCancer Discovery
Volume4
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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T-Lymphocytes
Hematopoietic Stem Cell Transplantation
T-Cell Antigen Receptor
Interleukin-2
Transplants
Immunomodulation
Regulatory T-Lymphocytes
Pharmaceutical Preparations
Immune System
Neoplasms
Antigens
Inhibition (Psychology)
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Shono, Y., Tuckett, A. Z., Ouk, S., Liou, H. C., Altan-Bonnet, G., Tsai, J. J., ... Zakrzewski, J. L. (2014). A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discovery, 4(5), 578-591. https://doi.org/10.1158/2159-8290.CD-13-0585
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. / A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. In: Cancer Discovery. 2014 ; Vol. 4, No. 5. pp. 578-591.
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abstract = "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.",
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Shono, Y, Tuckett, AZ, Ouk, S, Liou, HC, Altan-Bonnet, G, Tsai, JJ, Oyler, JE, Smith, OM, West, ML, Singer, NV, Doubrovina, E, Pankov, D, Undhad, CV, Murphy, GF, Lezcano, C, Liu, C, O'Reilly, RJ, van den Brink, MRM & Zakrzewski, JL 2014, 'A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity', Cancer Discovery, vol. 4, no. 5, pp. 578-591. https://doi.org/10.1158/2159-8290.CD-13-0585

A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. / 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, Vol. 4, No. 5, 01.01.2014, p. 578-591.

Research output: Contribution to journalArticle

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 - 2014/1/1

Y1 - 2014/1/1

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.

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