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| Pàgina inicial > Articles > Articles publicats > Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition |
(Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Universitat Autònoma de Barcelona. Departament de Medicina) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Joan XXIII de Tarragona) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia)
| Data: | 2020 |
| Resum: | Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10. 1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users. |
| Ajuts: | Instituto de Salud Carlos III PI17-00950 Instituto de Salud Carlos III PI17-00943 Instituto de Salud Carlos III PI18-01392 Instituto de Salud Carlos III PI16-01278 Ministerio de Ciencia e Innovación RYC-2012-12018 |
| Nota: | Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | PCNSL ; XPO1 ; BTK ; Innate immune system |
| Publicat a: | Journal of Neuro-Oncology, Vol. 149 (july 2020) , p. 13-25, ISSN 1573-7373 |
