Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

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

Authors: Mª Carmen Herrero-Sánchez, Concepción Rodríguez-Serrano, Julia Almeida, Laura San Segundo, Susana Inogés, Ángel Santos-Briz, Jesús García-Briñón, Luis Antonio Corchete, Jesús F. San Miguel, Consuelo del Cañizo, Belén Blanco

Published in: Journal of Hematology & Oncology | Issue 1/2016

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
Waickman AT, Powell JD. Mammalian target of rapamycin integrates diverse inputs to guide the outcome of antigen recognition in T cells. J Immunol. 2012;188:4721–9.CrossRefPubMedPubMedCentral
2.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.CrossRefPubMed
3.
Wu LX, La Rose J, Chen L, Neale C, Mak T, Okkenhaug K, et al. CD28 regulates the translation of Bcl-xL via the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway. J Immunol. 2005;174:180–94.CrossRefPubMed
4.
Appleman LJ, van Puijenbroek AA, Shu KM, Nadler LM, Boussiotis VA. CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells. J Immunol. 2002;168:2729–36.CrossRefPubMed
5.
Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303.CrossRefPubMedPubMedCentral
6.
Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010;32:743–53.CrossRefPubMedPubMedCentral
7.
8.
Abouelnasr A, Roy J, Cohen S, Kiss T, Lachance S. Defining the role of sirolimus in the management of graft-versus-host disease: from prophylaxis to treatment. Biol Blood Marrow Transplant. 2013;19:12–21.CrossRefPubMed
9.
Wolf D, von Lilienfeld-Toal M, Wolf AM, Schleuning M, von Bergwelt-Baildon M, Held SA, et al. Novel treatment concepts for graft-versus-host disease. Blood. 2012;119:16–25.CrossRefPubMed
10.
So L, Yea SS, Oak JS, Lu M, Manmadhan A, Ke QH, et al. Selective inhibition of phosphoinositide 3-kinase p110alpha preserves lymphocyte function. J Biol Chem. 2013;288:5718–31.CrossRefPubMed
11.
Blanco B, Herrero-Sanchez C, Rodriguez-Serrano C, Sánchez-Barba M, Del Cañizo MC. Comparative effect of two pan-class I PI3K inhibitors used as anticancer drugs on human T cell function. Int Immunopharmacol. 2015;28:675–85.CrossRefPubMed
12.
Blanco B, Herrero-Sanchez MC, Rodriguez-Serrano C, Sánchez-Barba M, Del Cañizo MC. Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms. Immunol Res. 2015;62:175–88.CrossRefPubMed
13.
Castor MG, Rezende BM, Bernardes PT, Vieira AT, Vieira EL, Arantes RM, et al. PI3Kgamma controls leukocyte recruitment, tissue injury, and lethality in a model of graft-versus-host disease in mice. J Leukoc Biol. 2011;89:955–64.CrossRefPubMed
14.
Taub DD, Murphy WJ, Asai O, Fenton RG, Peltz G, Key ML, et al. Induction of alloantigen-specific T cell tolerance through the treatment of human T lymphocytes with wortmannin. J Immunol. 1997;158:2745–55.PubMed
15.
Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte Jr J, Crawford JM, et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood. 1996;88:3230–9.PubMed
16.
Rolli-Derkinderen M, Machavoine F, Baraban JM, Grolleau A, Beretta L, Dy M. ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. J Biol Chem. 2003;278:18859–67.CrossRefPubMed
17.
Tomiyama H, Takata H, Matsuda T, Takiguchi M. Phenotypic classification of human CD8+ T cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector function. Eur J Immunol. 2004;34:999–1010.CrossRefPubMed
18.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–28.CrossRefPubMed
19.
Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:1851–63.CrossRefPubMed
20.
Furukawa S, Wei L, Krams SM, Esquivel CO, Martinez OM. PI3Kdelta inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV) + B cell lymphomas. Am J Transplant. 2013;13:2035–43.CrossRefPubMedPubMedCentral
21.
22.
Palaniappan M, Menon B, Menon KM. Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. Mol Cell Endocrinol. 2013;366:81–9.CrossRefPubMed
23.
Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science. 2010;328:1172–6.CrossRefPubMedPubMedCentral
24.
Vadlakonda L, Pasupuleti M, Pallu R. Role of PI3K-AKT-mTOR and Wnt signaling pathways in transition of G1-S phase of cell cycle in cancer cells. Front Oncol. 2013;3:85.PubMedPubMedCentral
25.
Fang Z, Zhang T, Dizeyi N, Chen S, Wang H, Swanson KD, et al. Androgen receptor enhances p27 degradation in prostate cancer cells through rapid and selective TORC2 activation. J Biol Chem. 2012;287:2090–8.CrossRefPubMed
26.
Barnhart BC, Lam JC, Young RM, Houghton PJ, Keith B, Simon MC. Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival. Cancer Biol Ther. 2008;7:1441–9.CrossRefPubMedPubMedCentral
27.
Nosrati N, Kapoor NR, Kumar V. Combinatorial action of transcription factors orchestrates cell cycle-dependent expression of the ribosomal protein genes and ribosome biogenesis. FEBS J. 2014;281:2339–52.CrossRefPubMed
28.
Chen S, Liu D, Wu J, Xu B, Lu K, Zhu W, et al. Effect of inhibiting the signal of mammalian target of rapamycin on memory T cells. Transplant Proc. 2014;46:1642–8.CrossRefPubMed
29.
Jung U, Foley JE, Erdmann AA, Toda Y, Borenstein T, Mariotti J, et al. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. Biol Blood Marrow Transplant. 2006;12:905–18.CrossRefPubMed
30.
Tomasoni R, Basso V, Pilipow K, Sitia G, Saccani S, Agresti A, et al. Rapamycin-sensitive signals control TCR/CD28-driven Ifnγ, Il4 and Foxp3 transcription and promoter region methylation. Eur J Immunol. 2011;41:2086–96.CrossRefPubMed
31.
Oh S, Hwang ES. The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. J Immunol Res. 2014;2014:589672.CrossRefPubMedPubMedCentral
32.
Hwang ES, Hong JH, Glimcher LH. IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508. J Exp Med. 2005;202:1289–300.CrossRefPubMedPubMedCentral
33.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74.PubMedPubMedCentral
34.
Valentino JD, Li J, Zaytseva YY, Mustain WC, Elliott VA, Kim JT, et al. Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. Clin Cancer Res. 2014;20:1212–22.CrossRefPubMedPubMedCentral
35.
Glimcher LH, Townsend MJ, Sullivan BM, Lord GM. Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol. 2004;4:900–11.CrossRefPubMed
36.
Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003;302:1041–3.CrossRefPubMed
37.
Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity. 2012;36:374–87.CrossRefPubMedPubMedCentral
38.
Slavik JM, Lim DG, Burakoff SJ, Hafler DA. Rapamycin-resistant proliferation of CD8+ T cells correlates with p27kip1 down-regulation and bcl-xL induction, and is prevented by an inhibitor of phosphoinositide 3-kinase activity. J Biol Chem. 2004;279:910–9.CrossRefPubMed
39.
Fischer K, Voelkl S, Berger J, Andreesen R, Pomorski T, Mackensen A. Antigen recognition induces phosphatidylserine exposure on the cell surface of human CD8+ T cells. Blood. 2006;108:4094–101.CrossRefPubMed
40.
Alam A, Cohen LY, Aouad S, Sekaly RP. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med. 1999;190:1879–90.CrossRefPubMedPubMedCentral
41.
Zheng Y, Yang J, Qian J, Zhang L, Lu Y, Li H, et al. Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone. J Mol Med (Berl). 2012;90:695–706.CrossRef
42.
McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009;69:5835–42.CrossRefPubMed
43.
Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res. 2009;315:485–97.CrossRefPubMed
44.
van Burik JA, Carter SL, Freifeld AG, High KP, Godder KT, Papanicolaou GA, et al. Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13:1487–98.CrossRefPubMed
45.
Powell JD, Lerner CG, Schwartz RH. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol. 1999;162:2775–84.PubMed
46.
Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol. 2007;178:2163–70.CrossRefPubMed
47.
Marty FM, Bryar J, Browne SK, Schwarzberg T, Ho VT, Bassett IV, et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110:490–500.CrossRefPubMedPubMedCentral
48.
Herrero-Sanchez MC, Rodriguez-Serrano C, Almeida J, San-Segundo L, Inogés S, Santos-Briz Á, et al. Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft-versus-host disease control. Br J Haematol. 2016;173:754–68.CrossRefPubMed
49.
Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, et al. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med Chem Lett. 2011;2:774–9.CrossRefPubMedPubMedCentral
50.
51.
Juchem KW, Anderson BE, Zhang C, et al. A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells. Blood. 2011;118:6209–19.CrossRefPubMedPubMedCentral
52.
Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med. 2005;11:1299–305.CrossRefPubMed
53.
Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63:249–79.CrossRefPubMed
54.
Shulman HM, Kleiner D, Lee SJ, Morton T, Pavletic SZ, Farmer E, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. pathology working group report. Biol Blood Marrow Transplant. 2006;12:31–47.CrossRefPubMed
55.
Kuykendall TD, Smoller BR. Lack of specificity in skin biopsy specimens to assess for acute graft-versus-host disease in initial 3 weeks after bone-marrow transplantation. J Am Acad Dermatol. 2003;49:1081–5.CrossRefPubMed
56.
Wang Y, Yu Q, He X, Romigh T, Altemus J, Eng C. Activation of AR sensitizes breast carcinomas to NVP-BEZ235’s therapeutic effect mediated by PTEN and KLLN upregulation. Mol Cancer Ther. 2014;13:517–27.CrossRefPubMed
57.
Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, et al. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One. 2013;8:e80070.CrossRefPubMedPubMedCentral
58.
Chiarini F, Grimaldi C, Ricci F, Tazzari PL, Evangelisti C, Ognibene A, et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res. 2010;70:8097–107.CrossRefPubMed
59.
Wong J, Welschinger R, Hewson J, Bradstock KF, Bendall LJ. Efficacy of dual PI-3K and mTOR inhibitors in vitro and in vivo in acute lymphoblastic leukemia. Oncotarget. 2014;5:10460–72.CrossRefPubMedPubMedCentral
60.
Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-gamma + IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 2012;72:581–91.CrossRefPubMed
61.
Choi EK, Jang HC, Kim JH, Kim HJ, Kang HC, Paek YW, et al. Enhancement of cytokine-mediated NF-kappaB activation by phosphatidylinositol 3-kinase inhibitors in monocytic cells. Int Immunopharmacol. 2006;6:908–15.CrossRefPubMed
62.
Xue Z, Li W, Wang H, Huang B, Ge Z, Gu C, et al. ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis. J Mol Med (Berl). 2014;92:1057–68.CrossRef
Metadata
Title
Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development
Authors
Mª Carmen Herrero-Sánchez
Concepción Rodríguez-Serrano
Julia Almeida
Laura San Segundo
Susana Inogés
Ángel Santos-Briz
Jesús García-Briñón
Luis Antonio Corchete
Jesús F. San Miguel
Consuelo del Cañizo
Belén Blanco
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0343-5

Other articles of this Issue 1/2016

Journal of Hematology & Oncology 1/2016 Go to the issue

Review

Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma

Research

Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

Erratum

Erratum to: Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines

Erratum

Erratum to: NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin

Review

How do we choose the best donor for T-cell-replete, HLA-haploidentical transplantation?

Research

Histologic and molecular analysis of patient derived xenografts of high-grade serous ovarian carcinoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits