Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

• MeSH
• chimerické antigenní receptory terapeutické užití   MeSH
• imunomodulace MeSH
• imunomodulační látky terapeutické užití   MeSH
• lenalidomid * terapeutické užití   MeSH
• lidé MeSH
• lymfom terapie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Lecithin:retinol acyltransferase (LRAT) is the major enzyme responsible for retinol esterification in the mammalian body. LRAT exhibits specific activity in the cells with active retinol metabolism where it converts retinols into retinyl esters, which represents the major storage form of retinol. Besides hepatic stellate cells in the liver, LRAT appears to have a key physiologic role in several other tissues. In this study, we generated a transgenic reporter mouse expressing green fluorescence protein (EGFP) under the control of region containing -1166 bps from promoter upstream from the putative transcriptional start site and 262 bps downstream of this start. Transgenic reporter mice exhibited specific expression in eyes and testes. In eyes, expression of EGFP-reporter is found in lens and lens epithelium and fibers from embryo to adulthood. In testes, LRAT-EGFP reporter is expressed both in Sertoli and in spermatocytes marking initiation of spermatogenesis in prepubertal mice. Our data show that the examined LRAT regulatory region is sufficient to achieve strong and selective expression in the eye and testes but not in liver and other organs.

• MeSH
• acyltransferasy genetika   MeSH
• epitel metabolismus   MeSH
• genetická transkripce genetika   MeSH
• genotyp MeSH
• meióza genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• oční čočka metabolismus   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• regulace genové exprese enzymů genetika   MeSH
• Sertoliho buňky metabolismus   MeSH
• spermatocyty ultrastruktura   MeSH
• spermatogeneze MeSH
• testis metabolismus   MeSH
• vitamin A metabolismus   MeSH
• vývojová regulace genové exprese genetika   MeSH
• zelené fluorescenční proteiny MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A tumor cell is formed when a critical amount of endogenous and/or exogenous tumorigenic stimuli is exceeded. We have shown that the transient presence of nontumorigenic stray cells in tissues of experimental animals that contain cells with a subcritical set of genetic mutations can act as a tumor-promoting stimulus. To induce somatic mutations in all chicken tissues, we have used the MAV-2 retroviral insertion system that almost exclusively generates nephroblastomas. MAV-2 mutagenized animals i.v. inoculated with nonmalignant cells developed early clonal lung tumors before nephroblastomas. Importantly, the injected cells did not become a component of resultant tumors. Lung tumors displayed specific mutational signature characterized by an insertion of MAV-2 provirus into the fyn-related kinase (frk) promoter that results in the overexpression of the frk gene. In contrast, plag1, foxP, and twist genes were most often mutagenized in nephroblastomas. Based on such observations, we propose the mechanism termed industasis, a promotion of fully malignant phenotype of incipient tumor cell by stray cells, and hypothesize that it might be the underlying cause of human multiple primary tumors.

• MeSH
• biologické modely MeSH
• buňky patologie   virologie   MeSH
• fyziologie virů MeSH
• invazivní růst nádoru MeSH
• inzerční mutageneze fyziologie   MeSH
• kultivované buňky MeSH
• kur domácí MeSH
• kuřecí embryo MeSH
• mnohočetné primární nádory etiologie   MeSH
• nádorová transformace buněk patologie   MeSH
• nádory ledvin patologie   virologie   MeSH
• nádory plic patologie   virologie   MeSH
• pohyb buněk fyziologie   MeSH
• proviry fyziologie   účinky léků   MeSH
• Wilmsův nádor patologie   virologie   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• zvířata MeSH

• MeSH
• DNA vazebné proteiny genetika   MeSH
• financování organizované MeSH
• geny ras genetika   MeSH
• integrace viru genetika   MeSH
• koncové repetice MeSH
• kuřecí embryo MeSH
• lidé MeSH
• mapování chromozomů MeSH
• nádory ledvin genetika   virologie   MeSH
• nemoci drůbeže genetika   MeSH
• onkogenní proteiny genetika   MeSH
• onkogeny genetika   MeSH
• polymerázová řetězová reakce MeSH
• proviry genetika   MeSH
• ptačí proteiny genetika   MeSH
• transkripční faktor Twist MeSH
• tumor supresorové geny MeSH
• virus ptačí myeloblastózy genetika   MeSH
• Wilmsův nádor genetika   virologie   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH