Subramaniam Malarkannan, PhD
Professor & Gardetto Chair for Immunology and Immunotherapy
Medicine (Hematology and Oncology)
Microbiology and Immunology
Medical College of Wisconsin
Senior Investigator, Blood Research Institute
Executive Member, DDRI, Clinical and Translational Science Institute
Research Focus: NK cell development and function
PhD: Madurai Kamaraj University, 1992, Human T cell Activation
Our laboratory studies the basic biology and clinical utilization of NK cells. The following are the major areas of our focus:
I. NK cell-mediated Immunotherapy
NK and T cells hold significant promise in formulating novel cellular immunotherapies targeted to chemo-resistant/relapsing malignant hematopoietic and solid tumors. Chimeric Antigen Receptor (CAR)-based NK or T cell-mediated cellular immunotherapy offers hope. However, CAR-mediated therapy also causes a deleterious pathological condition called, 'cytokine-release syndrome' (CRS), a potentially fatal condition. In this context, our lab is interested in defining the signaling cascades by which anti-tumor cytotoxicity and induction of inflammation are individually regulated in NK and T cells. Our recent study using unmanipulated NK cells identified a unique Fyn-ADAP-Carma1 signaling pathway that is exclusively responsible for the production of inflammatory cytokines, not anti-tumor cytotoxicity. We are currently working to engineer a ‘CRS-free-CAR’ therapy.
II. Spacetime relationship of signaling events in NK cells
Spaciotemporal organization of signaling events in lymphocytes are poorly understood. Hundreds of signaling molecules take part in transducing membrane proximal events into cellular functions. However, the precise mechanisms that co-ordinate and contain a pathway remain elusive. Scaffolding proteins provide insights into how signaling events can be spatiotemporally coordinated. IQGAP1 is a 190 kDa cytoplasmic scaffolding protein. Based on our preliminary work, we identify multiple scaffolding functions for IQGAP1. First, IQGAP1 regulates the terminal maturation and subset specification of NK cells. Second, IQGAP1 forms a novel signalosome around the perinuclear region to regulate ERK1/2 activation via Rac1→Pak→Raf→MEK1/2 pathway. Third, IQGAP1 plays a central role in actin polymerization, microtubule elongation and MTOC formation, which are important for the immunological synapse formation, tumor lysis and cell movement. Our work will provide crucial insights into how scaffolding proteins regulate the development, maturation and effector functions of NK cells.
III. Metabolic Reprogramming in NK Cells
NK Cells are crucial in mediating anti-tumor cytotoxicity. Transition of ‘resting’ to an ‘activated’ NK cell status requires a significant change in its bioenergetic requirements. However, the molecular mechanism that regulates this metabolic reprogramming in NK cells is yet to be defined. When and how NK cells switch to ‘Warburg’ metabolism is central to formulating successful therapeutic approaches of cancer treatment. Using two scaffold proteins, IQGAP1 and KSR1 that are predominantly expressed in lymphocytes, as molecular models we have uncovered a novel mechanism that is central to the metabolic reprogramming of NK cells. NK cells from Iqgap1-/-,Ksr1-/-, and Iqgap1-/-Ksr1-/- mice displayed a significantly impaired pattern of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), demonstrating an impaired mitochondrial function. In addition, lack of IQGAP1 and/or KSR1 significantly altered B-Raf/C-Raf→MEK1/2→ERK1/2→RSK1→ S6S235/S236 and PI3K-p85a→PDK1→AKT1T308→mTORC1→S6K1→S6S240/S244 signaling pathways. Results will provide novel insights into how two scaffold proteins IQGAP1 and KSR1 regulate the metabolic reprogramming of NK cells.