Genetic screen in myeloid cells identifies TNF-α autocrine secretion as a factor increasing MDSC suppressive activity via Nos2 up-regulation

• Verfasst von: Schröder, Matthias [VerfasserIn]
• Verfasst von: Krötschel, Marit [VerfasserIn]
• Verfasst von: Conrad, Lena [VerfasserIn]
• Verfasst von: Naumann, Svenja Kerstin [VerfasserIn]
• Verfasst von: Bachran, Christopher [VerfasserIn]
• Verfasst von: Rolfe, Alex [VerfasserIn]
• Verfasst von: Umansky, Viktor [VerfasserIn]
• Verfasst von: Helming, Laura [VerfasserIn]
• Verfasst von: Swee, Lee Kim [VerfasserIn]
• Titel: Genetic screen in myeloid cells identifies TNF-α autocrine secretion as a factor increasing MDSC suppressive activity via Nos2 up-regulation
• Verf.angabe: Matthias Schröder, Marit Krötschel, Lena Conrad, Svenja Kerstin Naumann, Christopher Bachran, Alex Rolfe, Viktor Umansky, Laura Helming, Lee Kim Swee
• E-Jahr: 2018
• Jahr: 07 September 2018
• Umfang: 12 S.
• Fussnoten: Published online: 07 September 2018 ; Gesehen am 27.04.2020
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Springer Nature, 2011
• Jahr Quelle: 2018
• Band/Heft Quelle: 8(2018) Artikel-Nummer 13399, 12 Seiten
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/s41598-018-31674-1
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1696785790

Abstract

The suppressive microenvironment of tumors remains one of the limiting factors for immunotherapies. In tumors, the function of effector T cells can be inhibited by cancer cells as well as myeloid cells including tumor associated macrophages and myeloid-derived suppressor cells (MDSC). A better understanding of how myeloid cells inhibit T cell function will guide the design of therapeutic strategies to increase anti-tumor responses. We have previously reported the in vitro differentiation of MDSC from immortalized mouse hematopoietic progenitors and characterized the impact of retinoic acid and 3-deazaneplanocin A on MDSC development and function. We describe here the effect of these compounds on MDSC transcriptome and identify genes and pathway affected by the treatment. In order to accelerate the investigation of gene function in MDSC suppressive activity, we developed protocols for CRISPR/Cas9-mediated gene editing in MDSC. Through screening of 217 genes, we found that autocrine secretion of TNF-α contributes to MDSC immunosuppressive activity through up-regulation of Nos2. The approach described here affords the investigation of gene function in myeloid cells such as MDSC with unprecedented ease and throughput.