Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch.

Autor:	Cornel AM; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands.; Center for Translational Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands., Dunnebach E; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands.; Center for Translational Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands., Hofman DA; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Das S; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; School of Biotechnology, KIIT University, Bhubaneswar, India., Sengupta S; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., van den Ham F; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Wienke J; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Strijker JGM; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., van den Beemt DAMH; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands.; Center for Translational Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands., Essing AHW; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Koopmans B; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Engels SAG; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Lo Presti V; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands.; Center for Translational Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands., Szanto CS; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., George RE; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Molenaar JJ; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., van Heesch S; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Dierselhuis MP; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands., Nierkens S; Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands S.Nierkens-2@prinsesmaximacentrum.nl.; Center for Translational Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Dec; Vol. 10 (12).
DOI:	10.1136/jitc-2022-005002
Abstrakt:	Background: Immunotherapy in high-risk neuroblastoma (HR-NBL) does not live up to its full potential due to inadequate (adaptive) immune engagement caused by the extensive immunomodulatory capacity of HR-NBL. We aimed to tackle one of the most notable immunomodulatory processes in neuroblastoma (NBL), absence of major histocompatibility complex class I (MHC-I) surface expression, a process greatly limiting cytotoxic T cell engagement. We and others have previously shown that MHC-I expression can be induced by cytokine-driven immune modulation. Here, we aimed to identify tolerable pharmacological repurposing strategies to upregulate MHC-I expression and therewith enhance T cell immunogenicity in NBL. Methods: Drug repurposing libraries were screened to identify compounds enhancing MHC-I surface expression in NBL cells using high-throughput flow cytometry analyses optimized for adherent cells. The effect of positive hits was confirmed in a panel of NBL cell lines and patient-derived organoids. Compound-treated NBL cell lines and organoids were cocultured with preferentially expressed antigen of melanoma (PRAME)-reactive tumor-specific T cells and healthy-donor natural killer (NK) cells to determine the in vitro effect on T cell and NK cell cytotoxicity. Additional immunomodulatory effects of histone deacetylase inhibitors (HDACi) were identified by transcriptome and translatome analysis of treated organoids. Results: Drug library screening revealed MHC-I upregulation by inhibitor of apoptosis inhibitor (IAPi)- and HDACi drug classes. The effect of IAPi was limited due to repression of nuclear factor kappa B (NFκB) pathway activity in NBL, while the MHC-I-modulating effect of HDACi was widely translatable to a panel of NBL cell lines and patient-derived organoids. Pretreatment of NBL cells with the HDACi entinostat enhanced the cytotoxic capacity of tumor-specific T cells against NBL in vitro, which coincided with increased expression of additional players regulating T cell cytotoxicity (eg, TAP1/2 and immunoproteasome subunits). Moreover, MICA and MICB, important in NK cell cytotoxicity, were also increased by entinostat exposure. Intriguingly, this increase in immunogenicity was accompanied by a shift toward a more mesenchymal NBL cell lineage. Conclusions: This study indicates the potential of combining (immuno)therapy with HDACi to enhance both T cell-driven and NKcell-driven immune responses in patients with HR-NBL. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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