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

Background: The MYC oncogene drives T and B cell lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Such lymphomas are said to be "oncogene-addicted" to MYC. In order to develop targeted therapies for MYC-driven cancers, it is vital to understand how MYC regulates both cell autonomous and non-cell-autonomous processes, including host immunity.

Approach: We have used a particularly tractable approach for studying the role of oncogenic MYC on the host immune system during lymphomagenesis through a tetracycline (tet)-system regulated transgenic mouse model of MYC-driven T cell lymphoma (SRα-tTA/Tet-O-MYC mice; Felsher and Bishop, Molecular Cell, 1999). By delineating the global immunological changes during primary MYC-driven T cell lymphomagenesis in SRα-tTA/Tet-O-MYC mice using mass cytometry (CyTOF) and CIBERSORT, we identified anti-tumor immune subsets that can be developed as therapies to treat MYC-driven lymphomas.

Results: Amongst the immune subsets evaluated, our results demonstrated a specific systemic suppression of natural killer (NK) cell-mediated surveillance in SRα-tTA/Tet-O-MYC mice bearing overt MYC-driven T cell lymphomas. Inactivation of lymphoma-intrinsic MYC restores NK cell-mediated immune surveillance, suggesting that the regulation of NK cell-mediated surveillance may be integral to MYC-induced lymphomagenesis. We observed that lymphoma-specific MYC transcriptionally represses STAT1/2 and secretion of Type I Interferons (IFNs) required for normal NK cell homeostasis and NK cell-mediated immune surveillance in the tumor microenvironment. Concordantly, treating T cell lymphoma-bearing SRα-tTA/Tet-O-MYC mice with Type I IFN improves survival by rescuing NK cell production, and in part overriding MYC-mediated suppression of NK surveillance. We showed that human lymphomas with both high levels of MYC and low levels of STAT1/2 have lower NK surveillance, and are associated with poor prognosis. Finally, we established the therapeutic implications of our findings by showing that adoptive transfer of NK cells significantly delays lymphoma initiation, and recurrence after MYC inactivation; suggesting that NK cell-based therapy may be effective against MYC-driven lymphomas.

Conclusion: Subversion of NK cell surveillance is integral to MYC-induced lymphomagenesis. Our studies provide a rationale for further developing the NK subset as a cell-based immunotherapy to effectively treat MYC-driven lymphomas in the future.