Dataset Information

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition.

ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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 SIRP?. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRP? expression in the remaining tumor-promoting M2-like macrophages. CONCLUSIONS: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.

SUBMITTER: Jimenez I

PROVIDER: S-EPMC7452938 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition.

Jiménez Isabel I Carabia Júlia J Bobillo Sabela S Palacio Carles C Abrisqueta Pau P Pagès Carlota C Nieto Juan C JC Castellví Josep J Martínez-Ricarte Francisco F Escoda Lourdes L Perla Cristóbal C Céspedes Torrez Dennis H DH Boix Joan J Purroy Noelia N Puigdefàbregas Lluís L Seoane Joan J Bosch Francesc F Crespo Marta M

Journal of neuro-oncology 20200720 1

<h4>Background</h4>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 recen ...[more]

PMID: 32691208

Similar Datasets

Project description:Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.

Dataset Information

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition.

Publications

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets