期刊
CANCER DISCOVERY
卷 4, 期 5, 页码 578-591出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0585
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资金
- NIH [R01-HL069929, R01-AI100288, R01-AI080455, R01-AI101406, 1K08CA160659-01]
- Leukemia Research Foundation
- Radiation Effects Research Foundation (RERF-NIAID)
- Uehara Memorial Foundation
- Lymphoma Research Foundation Post-Doctoral Fellowship Research Grant
- MSKCC Center for Molecular Imaging and Nanotechnology (CMINT)
- Experimental Therapeutics Center of MSKCC
- Lymphoma Foundation
- Alex's Lemonade Stand
- Geoffrey Beene Cancer Research Center at MSKCC
- Peter Solomon Fund
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. (C) 2014 AACR.
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