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

Abstract

34The MYC oncogene drives T and B lymphoid malignancies, including Burkitt's lymphoma (BL) 35and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction 36 in natural killer (NK) cell-mediated surveillance in SRα-tTA/Tet-O-MYC ON mice bearing MYC-37driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic 38 MYC releases the brakes on NK maturation restoring NK homeostasis. Lymphoma-intrinsic 39 MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I 40 Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by 41 rescuing NK cell maturation. In MYC-driven BL patients, low expression of both STAT1 and 42 STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable 43 clinical outcomes. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma 44 growth and recurrence post MYC inactivation. Our studies thus provide a rationale for 45 developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future. 46Oncogene addiction is the phenomenon where a cancer becomes causally dependent on a single 47 'driver' oncogene for the maintenance of its proliferation and survival 1,2 . Inhibition of the driver 48 oncogene forms the basis of oncogene targeted therapy 1-3 . Hence, a potential Achilles' heel of 49 human malignancies lies in their addiction to oncogenes such as MYC, RAS and BCR-ABL1 4,5 . 50Targeted therapy has been successful against BCR-ABL1 (Philadelphia/Ph + )-induced leukemia 51 6,7 , while therapies that successfully target MYC or RAS remain to be developed. 52In order to develop targeted therapies for MYC-driven cancers, it is vital to understand 53 whether MYC regulates both cell autonomous and non-autonomous processes, including host 54 immunity. Oncogene addiction was previously assumed to be cell autonomous and immune-55 independent 8 . Many recent studies illustrate that MYC and other oncogenes alone or 56 cooperatively may regulate the tumor microenvironment and host immune responses in multiple 57 tumor types 9-16 . In particular, two reports highlighted that oncogenes may cooperate to more 58 globally regulate the host immune system 12,16 . 59We have used a particularly tractable approach for studying the role of the host immune 60 system during MYC-driven tumorigenesis through tetracycline (tet)-system regulated transgenic 61 mouse models of cancer. Our inducible mouse models enable us to study how MYC inactivation 62 elicits tumor regression through both cancer-intrinsic and cancer-extrinsic host immune-63 dependent mechanisms 11,13 . CD4 + T cells appear to be essential for the sustained regression of 64 cancers upon MYC inactivation 11,13 . However, the changes in immune landscape during primary 65 MYC-induced tumorigenesis in these models remain to be delineated. 66Our goal was to delineate the global immunological changes resulting from primary overt 67 MYC-driven lymphomagenesis, to identify...

Arrested development: suppression of NK cell function in the tumor microenvironment

“…Tumor‐bearing mice displayed reduced levels of interleukin (IL)‐15R⍺ + in BM stromal cells, and transgenic IL‐15 expressing mice restored NK cell anti‐tumor function indicating that IL‐15R⍺ expression BM stromal cells can be suppressed during tumorigenesis in the BM niche 23 . In support of this hypothesis, a recent study using a mouse transgenic MYC‐driven T‐lymphoma model observed reduced mNK cells in peripheral organs due to suppressed NK cell development in the BM 26 . Type I interferon (IFN) signalling was suppressed in the BM microenvironment in the presence of MYC‐driven lymphomas, and type I IFN was found to be required for systemic mNK cell development 26 .…”

“…23 In support of this hypothesis, a recent study using a mouse transgenic MYC-driven T-lymphoma model observed reduced mNK cells in peripheral organs due to suppressed NK cell development in the BM. 26 Type I interferon (IFN) signalling was suppressed in the BM microenvironment in the presence of MYC-driven lymphomas, and type I IFN was found to be required for systemic mNK cell development. 26 Since type I IFN is known to induce IL-15R⍺ on dendritic cells (DCs), 27 a potential decrease in IL-15R⍺ + BM DCs could explain the block in NK cell development during lymphoma development in the BM.…”

Metabolic Convergence on Lipogenesis in RAS, BCR-ABL, and MYC-driven Lymphoid Malignancies

“…3D). Previously published experiments using this model in a MYC on vs MYC off vs murine background clearly shows a preference for lipogenesis pathway upregulation in a MYC positive state (32). Thus, in high MYC expressing lymphomas, reliance upon fatty acid synthesis could be considered a metabolic liability.…”

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

“…Two studies further investigated consequences of MYC overexpression on NK cell-mediated cytotoxicity. Investigating the systemic effects of Myc in murine T cell lymphomas a recent study showed that Myc expression was associated with lower NKp46 + NK cells in circulation, lower NK cell maturation and more disease progression than control mice [ 88 ]. In contrast, another study reported that MYC mRNA levels in B cell lymphomas and solid tumors are positively correlated with B7-H6 expression on the tumor cell, a ligand for the NK cell receptor NKp30.…”