Tumor Environment Promotes Lnc57Rik-Mediated Suppressive Function of Myeloid-Derived Suppressor Cells [TUMOR IMMUNOLOGY]

Key Points

Lnc57Rik can be induced by tumor-associated factors.

Lnc57Rik promotes the immunosuppressive function of MDSCs.

Lnc57Rik binds with the C/EBPβ isoform LAP and WDR5.

Visual AbstractFigureFigureAbstract

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity that regulate immune responses in the tumor microenvironment. We identified a novel long noncoding RNA (lncRNA), named as lnc57Rik, in the MDSCs that controls their immunosuppressive functions. Lnc57Rik was induced in in vitro and in vivo inflammatory settings and upregulated the genes related to MDSC-mediated immunosuppression, including Arg-1, NOS2, NOX2, and COX2. Furthermore, Lnc57Rik can not only bind with the C/EBPβ isoform liver-enriched activator protein to activate C/EBPβ but also with the methyltransferase WD repeat-containing protein 5 that enables the enrichment of histone H3 trimethylated lysine 4 marks on the promoter regions of Arg-1, NOS2, NOX2, and COX2, eventually resulting in their transcriptional activation. Furthermore, the conserved human lnc57Rik has a similar function as murine lnc57Rik. Taken together, upregulation of lnc57Rik in the tumor microenvironment promotes the immunosuppressive function of MDSCs.

Footnotes

This work was supported by the National Natural Science Foundation of China (91842302, 81970488, 81970457, and 91629102), Tianjin Science and Technology Commission (20JCQNJC01780 and 18JCZDJC35300), Ministry of Science and Technology (2016YFC1303604), and the State Key Laboratory of Medicinal Chemical Biology and the Fundamental Research Funds for the Central Universities, Nankai University (63191724).

The online version of this article contains supplemental material.

Abbreviations used in this article:

AOMazoxymethaneArg-1arginase-1ASH2Lhomeotic 2-like proteinBMbone marrowBMCbone marrow cellChIPchromatin immunoprecipitationCHOPC/EBP homologous proteinCOX2cyclooxygenase-2CSK, cytoskeletal; DCdendritic cellDCFDA, dichlorodihydrofluorescein diacetate; DSSdextran sodium sulfateFISHfluorescence in situ hybridizationH3K4me3histone H3 trimethylated lysine 4H2O2hydrogen peroxideIPimmunoprecipitationKOknockoutlncRNAlong noncoding RNALAP, liver-enriched activator protein; MDSCmyeloid-derived suppressor cellMLLmixed lineage leukemia proteinNOS2NO synthase 2NOX2NADPH oxidase 2PMN-MDSCpolymorphonuclear myeloid-derived suppressor cellqPCRquantitative PCRqRT-PCRquantitative real-time PCRRIPRNA immunoprecipitationROSreactive oxygen speciessiRNAsmall interfering RNAWDR5WD repeat-containing protein 5WTwild typeReceived March 15, 2022.Accepted July 22, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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