Notch inhibition enhances graft-versus-leukemia while reducing graft-versus-host disease

• Published in: European journal of pharmacology 2019-01, Vol.843, p.226-232
• Main Authors: Luo, Xiaodan, Xu, Lihua, Liu, Lian, Li, Yangqiu, Tan, Huo
• Format: Article
• Language: English
• Subjects: Cancer; Graft-versus-host disease; Leukemia; Notch; Transplantation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2018.10.004

Graft-versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dissociation of graft versus-leukemia (GVL) activity from GVHD has yet to be achieved. In this study, we used γ-secretase inhibitor (GSIs, DAPT) to inhibit Notch signaling in GVHD and GVL murine model. We found that CD11c+CD80+ dendritic cells (DCs) were up-regulated but did not enhance GVHD. Regulatory T cells (Tregs) and central memory T cells that express high levels of CD62L and CD44 had an expansion after Notch inhibition. Reduced Tumor Necrosis Factor-α and increased Interferon-γ production were found, which might be ascribed to the expansion of Tregs and central memory T cells, and result in increased sensitivity of tumor cells to cytotoxic T lymphocyte activity. Fas Receptor-Fas Ligand interaction plays a critical role in GVL instead of aGVHD. Fas Ligand expressions were similar in recipients with or without Notch inhibition, suggesting that GVL activity was maintained. We showed that Notch inhibition could enhances GVL while reducing GVHD via modulating host DCs and donor T cell activity, and the production of inflammatory cytokines. Graphic Abstract: Notch inhibition by DAPT enhances GVL while reducing GVHD. Notch inhibition up-regulated host CD11c+ DCs and increased the surface expression of CD80 on CD11c+ DCs without enhancing GVHD. Tregs and central memory T cells that express high levels of CD62L and CD44 had an expansion, which can differentiate into effector T cells and express cytolytic functions. Reduced TNF-α and Increased IFN-γ levels might be ascribed to the expansion of Tregs and central memory T cells and result in increased sensitivity of tumor cells to CTL activity. [Display omitted]