MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

Srividya Swaminathan, Line D. Heftdal, Daniel F. Liefwalker, Renumathy Dhanasekaran, Anja Deutzmann, Crista Horton, Adriane Mosley, Mariola Liebersbach, Holden T. Maecker, and Dean W. Felsher

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Jun 13, 2019
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Received Date: 23rd October 18

The MYC oncogene drives T and B lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction in natural killer (NK) cell-mediated surveillance in SRa-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic MYC releases the brakes on NK maturation restoring NK homeostasis. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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