A large number of lymphoid neoplasms are currently being treated with conventional chemotherapies that are toxic for normal cells. Of note, healthy lymphocytes express the normal counterparts of oncoproteins, making direct targeting of oncogenes difficult. Therefore, identification of therapies that can specifically target cancer cells is required. The immune system is a natural defense mechanism against cancers that can be activated to specifically kill malignant cells.

Development of targeted immunotherapy against lymphoid malignancies requires distinguishing normal and malignant lymphocytes in two respects: (1) Cell-intrinsic signaling, that includes surface molecules and intracellular signaling, and (2) Regulation of immune microenvironment. Srividya Swaminathan’s laboratory will study these aspects by comparing both cell-intrinsic processes, and the spatial and temporal distribution of the immune system during normal and malignant lymphopoiesis; using approaches including mass cytometry (CyTOF), CIBERSORT and humanized mouse models. This knowledge will be applied for the development of cell-based and other immunotherapies. Her laboratory at the City of Hope is currently funded by a five‐year start‐up package, the American Society of Hematology (ASH) Scholar Award, the NCI Lymphoma SPORE Career Enhancement Program, and a Research Starter Grant from the PhRMA Foundation.

Research Highlights

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, 2020; 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.