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.
Highlights
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL)
SRα restricts the overexpression of the human MYC transgene to the T cell lineage in SRα-tTA/tetO-MYC mice, giving rise to systemically disseminated Tlymphomas[1]
The center is at the median, minima and maxima are indicated by whiskers, and the box represents data between the 25th and 75th percentile
Summary
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). To develop targeted therapies for MYC-driven cancers, it is vital to understand how MYC regulates cell-autonomous and non-autonomous processes, including host immunity. We use tractable approaches for studying the role of the host immunity during MYC-driven tumorigenesis through tetracycline (tet)-system regulated transgenic mouse models of cancer. These models enable us to understand how MYC inactivation elicits tumor regression through cancer-intrinsic and extrinsic host immune-dependent mechanisms[1,10,15]. Using mass cytometry (CyTOF), we examine specific changes in the host immune composition upon MYC activation as well as after subsequent MYC inactivation in situ in SRα-tTA/tet-O-MYC mice predisposed to developing MYC-driven T cell lymphoblastic lymphoma[1]. Our results provide a rationale for developing and combining NK cell-based therapies with MYC inhibitors to treat MYC-driven lymphomas
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