MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

Srividya Swaminathan, Aida S. Hansen, Line D. Heftdal, Renumathy Dhanasekaran, Anja Deutzmann, Wadie D. M. Fernandez, Daniel F. Liefwalker, Crista Horton, Adriane Mosley, Mariola Liebersbach, Holden T. Maecker and Dean W. Felsher ()
Additional contact information
Srividya Swaminathan: Stanford University
Aida S. Hansen: Stanford University
Line D. Heftdal: Stanford University
Renumathy Dhanasekaran: Stanford University
Anja Deutzmann: Stanford University
Wadie D. M. Fernandez: Stanford University
Daniel F. Liefwalker: Stanford University
Crista Horton: Stanford University
Adriane Mosley: Stanford University
Mariola Liebersbach: Stanford University
Holden T. Maecker: Stanford University School of Medicine
Dean W. Felsher: Stanford University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. 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. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. 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. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

Date: 2020
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DOI: 10.1038/s41467-020-16447-7

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