Constitutively active GSK3 beta as a means to bolster dendritic cell functionality in the face of tumor-mediated immune suppression

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Gonzalez , M L , Oosterhoff , D , Lindenberg , J J , Milenova , I , Lougheed , S M , Martianez , T , Dekker , H , Quixabeira , D C A , Hangalapura , B , Joore , J , Piersma , S R , Cervera-Carrascon , V , Santos , J M , Scheper , R J , Verheul , H M W , Jimenez , C R , Van De Ven , R , Hemminki , A , Van Beusechem , V W & De Gruijl , T D 2019 , ' Constitutively active GSK3 beta as a means to bolster dendritic cell functionality in the face of tumor-mediated immune suppression ' , OncoImmunology , vol. 8 , no. 10 , e1631119 . https://doi.org/10.1080/2162402X.2019.1631119

Title: Constitutively active GSK3 beta as a means to bolster dendritic cell functionality in the face of tumor-mediated immune suppression
Author: Gonzalez, Marta Lopez; Oosterhoff, Dinja; Lindenberg, Jelle J.; Milenova, Ioanna; Lougheed, Sinead M.; Martianez, Tania; Dekker, Henk; Quixabeira, Dafne Carolina Alves; Hangalapura, Basav; Joore, Jos; Piersma, Sander R.; Cervera-Carrascon, Victor; Santos, Joao Manuel; Scheper, Rik J.; Verheul, Henk M. W.; Jimenez, Connie R.; Van De Ven, Rieneke; Hemminki, Akseli; Van Beusechem, Victor W.; De Gruijl, Tanja D.
Contributor: University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Department of Oncology
Date: 2019-10-03
Language: eng
Number of pages: 18
Belongs to series: OncoImmunology
ISSN: 2162-402X
URI: http://hdl.handle.net/10138/306058
Abstract: In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and in vivo vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3 beta (GSK3 beta) as a pivotal kinase in both DC development and suppression. GSK3 beta inhibition blocked human DC differentiation in vitro, which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3 beta induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an in vivo melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3 beta activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.
Subject: Dendritic cell
differentiation
maturation
IL-10
GSK3 beta
kinase profiling
tumor microenvironment
INDUCED INHIBITION
IL-10 PREVENTS
LINE MODEL
T-CELLS
DIFFERENTIATION
CANCER
P38
PROMOTES
ACTIVATION
MATURATION
3122 Cancers
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