MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Authors: 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 & Dean W. Felsher
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.
Reference: Swaminathan, S., Hansen, A.S., Heftdal, L.D. et al. MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies. Nat Commun 11, 2860 (2020). Retrieved from https://www.nature.com