Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Journal of Hematology & Oncology, Oct 2016

Background Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.

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Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Herrero-Sánchez et al. Journal of Hematology & Oncology Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft- versus-host disease development Mª Carmen Herrero-Sánchez 0 1 Concepción Rodríguez-Serrano 0 1 Julia Almeida 0 Laura San Segundo 0 Susana Inogés Ángel Santos-Briz 0 Jesús García-Briñón 0 Luis Antonio Corchete 0 1 Jesús F. San Miguel Consuelo del Cañizo 0 1 Belén Blanco 0 1 0 Instituto de Investigación Biomédica de Salamanca (IBSAL) , Paseo de San Vicente 58-182, 37007 Salamanca , Spain 1 Servicio de Hematología, Hospital Universitario de Salamanca , Paseo de San Vicente 58-182, 37007 Salamanca , Spain Background: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis. Hematopoietic stem cell transplantation; Graft-versus-host disease; T cell; PI3K/AKT/mTOR pathway; PI3K inhibitor - Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for many hematologic malignancies. Unfortunately, a serious complication is frequently developed after allo-HSCT: graft-versus-host disease (GvHD). GvHD occurs when donor T lymphocytes recognize as foreign and destroy patient’s healthy tissues. Despite the immunosuppressive regimens administered, GvHD remains the major cause of morbidity and mortality after allo-HSCT. Thus, new therapeutic strategies are needed. One of the key signaling pathways involved in T cell activation and function is phosphatidylinositol 3-kinase/ AKT/mammalian target of rapamycin (PI3K/AKT/ mTOR) [1]. This pathway controls numerous cellular processes, including proliferation, survival, migration, and metabolism [2]. In particular, PI3K activation in T cells promotes survival [3] and cell cycle progression [4], modulates differentiation [5, 6], and controls the acquisition of effector and memory phenotypes [7]. Thus, inhibitors of PI3K/AKT/mTOR pathway can interfere with T cell activation and function. The use of PI3K/AKT/mTOR inhibitors has been scantily explored in the allo-HSCT context. Only the © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. utility of the mTORC1 inhibitor rapamycin (Sirolimus) has been extensively studied, providing promising results [8]. In addition, it has been suggested that the beneficial effects observed in patients with chronic GvHD treated with tyrosine kinase inhibitors could be due, in part, to their ability to inhibit PI3K signaling in T cells [9]. However, few studies have evaluated the immunosuppressive effect of PI3K inhibitors on T lymphocytes [10–12] and their ability to prevent GvHD development [13, 14]. Herein, we have analyzed the effects of two novel antitumor drugs, the pan-class I PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235, on T cell activation and evaluated the utility of BEZ235 in a murine model of GvHD. Methods Drugs BEZ235 was kindly provided by Novartis Pharma (Basel, Switzerland). BKM120 was purchased from Selleck Chemicals (Houston, TX, USA). For in vitro studies, BKM120 and BEZ235 were reconstituted in DMSO at 10 mM and stored (...truncated)


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Mª Herrero-Sánchez, Concepción Rodríguez-Serrano, Julia Almeida, Laura San Segundo, Susana Inogés, Ángel Santos-Briz, Jesús García-Briñón, Luis Corchete, Jesús San Miguel, Consuelo del Cañizo, Belén Blanco. Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development, Journal of Hematology & Oncology, 2016, pp. 113, 9, DOI: 10.1186/s13045-016-0343-5