Many B and T cell neoplasms including Burkitt’s Lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL) are “addicted” to oncogenes for their survival and recurrence. Oncogenic MYC, ABL, RAS and MLL differentially regulate both cell-autonomous processes as well as cell non-autonomous processes (cancer microenvironment and host immunity), in comparison to their normal counterparts.
Recently, using mass cytometry (CyTOF), Dr. Swaminathan profiled the immune microenvironment around MYC oncogene-driven T cell lymphoma. She identified a novel mechanism by which oncogenic MYC directly and reversibly remodels the systemic immune landscape during primary murine T cell lymphomagenesis. Amongst the immune compartments modulated by oncogenic MYC during primary lymphomagenesis, she identified a specific exclusion of natural killer (NK) cells from the lymphoma microenvironment. She found that lymphoma-intrinsic MYC arrests NK cell maturation by transcriptionally repressing STAT1 and STAT2, and the subsequent secretion of Type I Interferons (IFNs). MYC inactivation in malignant T-lymphocytes restored Type I IFN signaling and recruited NK cells into the lymphoma microenvironment (Swaminathan et al., Nature Communications, in revision; BioRxiv, 2018; Figure below).
Dr. Swaminathan’s studies suggest that NK cells can be developed as an adoptive cell-based immunotherapy against MYC and other oncogene-driven lymphomas. The development of immune cell-based therapeutics as an alternative to direct oncogene inhibition will be one of the areas of her laboratory’s research focus. In order to develop both cell-based and non cell-based immunotherapies, her laboratory will delineate the differences between lymphoma cell-intrinsic and extrinsic (host immunity) processes during normal and malignant lymphopoiesis in vivo.