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Subramaniam Malarkannan, PhD

Subramaniam Malarkannan, PhD

Senior Investigator & Gardetto Chair for Molecular Immunology and Immunotherapy

Laboratory of Molecular Immunology and Immunotherapy
Versiti Blood Research Institute, Versiti Blood Center of Wisconsin

Professor 
Department of Medicine-Hematology & Oncology, 
Department of Microbiology & Immunology,
Department of Pediatrics, and
Clinical and Translational Science Institute (CTSI)
Medical College of Wisconsin

Member, Center for Excellence for Prostate Cancer Research,
Cancer Center of Southeastern Wisconsin

Executive Council Member
Drug Discovery & Repurposing Initiative
CTSI

Postdoctoral Training
UC Berkeley

Doctoral Training
Madurai Kamaraj University, Madurai, India

Contact Us

Subramaniam Malarkannan, PhD

Senior Investigator & Gardetto Chair for Molecular Immunology and Immunotherapy
Email (414) 937-3812

  • Research Interests

    Our laboratory studies the basic biology and clinical utilization of NK cells. The following are the major areas of our focus:

    NK cell-mediated Immunotherapy

    NK and T cells hold significant promise in the formulations of novel cellular immunotherapies targeted to chemo-resistant/relapsing malignant hematopoietic and solid tumors. More importantly, recent scientific breakthroughs have helped to formulate a successful Chimeric Antigen Receptor (CAR)-based NK or T cell-mediated cellular immunotherapy. However, CAR-mediated therapy also causes a deleterious pathological condition called, 'cytokine-release syndrome' (CRS), a potentially fatal condition in two thirds of patients. CRS is a direct outcome of CAR therapy and is caused by a significantly augmented production of inflammatory cytokines by CAR-transduced lymphocytes. Two thirds of the patients infused with CAR-transduced lymphocytes develop differing levels of CRS. Formulations of novel methods that regulate inflammation are of high clinical relevance and are central to prevent CRS.

    Our current work focuses on generating NK cell-based novel immunotherapies. Our clinical group headed by Dr. Monica Thakar currently offers an unmanipulated NK cell-based immunotherapy to cancer patients. She employs a cellular and adoptive immunotherapy strategy that incorporates hematopoietic cell transplantation (HCT) followed by the infusion of donor-derived NK cells into cancer patients. Clinical grade NK cells are manufactured under FDA-approved IND BB 13794 (Dr. Thakar) and infused into the patients. This therapy is being offered at the Children’s Hospital of Wisconsin and Froedtert Hospital. In addition, we are interested in defining the precise molecular mechanisms by which anti-tumor cytotoxicity and induction of inflammation are individually regulated in NK and T cells. This molecular blueprint is central to the success of the CAR-mediated clinical applications. In this context, 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 (61/866,348; 8/15/2013). We are currently working to engineer a ‘CRS-free-CAR’ therapy.

    Spacetime relationship of signaling events in NK cells

    Spaciotemporal organization of signaling events in lymphocytes are poorly understood.  Ligands initiate multiple signaling pathways via unique receptors. Hundreds of signaling molecules take part in transducing membrane proximal events into meaningful cellular functions. Although exceptional advances made in the understanding of signaling cascades, the precise mechanisms that co-ordinate and contain a pathway remain elusive. Scaffolding proteins have provided part of the explanation into how signaling events can be spatiotemporally co-ordinated. IQGAP1 is a 190 kDa cytoplasmic scaffolding protein.  Here, we are working to determine how the spacetime relativity of specific signaling events is controlled by IQGAP1. We hypothesize that IQGAP1 functions as a signal processing center. Based on our preliminary work, we identify multiple major scaffolding functions for IQGAP1.  First, IQGAP1 regulates β-catenin/TCF/LEF activation pathway that is involved in 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.

    Results obtained from these aims will provide crucial insights into how a unique scaffolding protein regulates the development, maturation and effector functions of NK cells. These studies will also provide critical understanding of how IQGAP1 organizes membrane proximal signaling events into distal signalosomes that transiently but abundantly generate phosphorylated kinases and substrates in the perinuclear region of an effector lymphocyte.

    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. Lack of either or both IQGAP1 and KSR1 resulted in significant alteration in the ability of NK cells to switch from a primarily oxidative phosphorylation to aerobic glycolysis. Both mitochondrial function and the ability to increase the mitochondrial mass are defective in the absence of IQGAP1 and KSR1.  More importantly, 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. We hypothesize that IQGAP1 and KSR1 act as central core of a signaling complex that is indispensable for metabolic reprogramming in effector lymphocytes; therefore, their ability to mediating anti-tumor cytotoxicity and production of inflammatory cytokines/chemokines.

    Results obtained through these specific aims will provide novel insights into how two scaffold proteins IQGAP1 and KSR1 regulate the metabolic reprogramming of NK cells. Since these scaffold proteins are expressed primarily in hematopoietic cells, we predict these results will be applicable to other effector lymphocytes.

  • Grant Support
    • Nicholas Family Foundation, "NK cell-based Immunotherapies," Role: PI (10/01/2014 - 09/30/2019)
    • High Risk Hematological Malignancies Program - MACC-Fund Initiatives, "Novel CAR-based Immunotherapeutic Approaches to Pediatric Cancer," Role: PI (07/01/2014 - 06/30/2019)
    • NCI, 1R01 CA179363, "Molecular signature of inflammation," Role: PI (03/10/2014 - 02/28/2019)
    • NIH-NIAID, R01 AI102893, "Molecular mechanisms of signaling co-ordination in innate lymphocytes," Role: PI (08/01/2013 - 07/31/2017)
    • Alex's Lemonade Stand Foundation, "Control of inflammation in genetically-modified lymphocytes," Role: PI (09/01/2013-08/30/2014)
    • Clinical and Translational Science Institute, "Cellular and adoptive immunotherapy using hematopoietic cell transplantation and NK cell infusion for the treatment of high risk pediatric and adult solid tumors: a Phase I/II Study," Role: Co-I (07/01/2012 - 06/30/2014)
    • American Cancer Society Pilot Research Grant, "NK cell immunotherapy in relapsed and refractory solid tumors," Role: Co-I (07/01/2012 - 06/30/2014)
    • MACC-Fund Novel Initiatives, "Cellular therapy using haploidentical donor NK cells," Role: PI (07/01/2012 - 06/30/2014)
  • Lab

    Subramaniam Malarkannan, PhD
    PI, Molecular Immunology and Immunotherapy
    Professor of Medicine - Hematology and Oncology & Microbiology and Molecular Genetics
    Senior Investigator, Blood Research Institute

    Research Interests: We are interested in the basic biology and clinical utilization of NK cells.  In particular, we study signaling cascades in muring and human NK cells.  This helps us to correlate the role of individual signaling proteins with the development, terminal maturation and effector functions on NK cells.  Using our findings, we are also exploring the translational relevance of NK and T cells.  

    Email: SMalarkannan@Versiti.org

    Monica Thakar, MD 
    Assistant Professor of Pediatrics - Hematology and Oncology
    Clinical & Co-PI, Molecular Immunology and Immunotherapy

    Research Interests:  As a physician scientist who has specialized in hematopoietic cell transplantation, my clinical and translational research is geared toward using cellular therapies to treat both malignant and non-malignant (genetic) diseases.  I am currently evaluating the role of hematopoietic cell transplantation and adoptive immunotherapy with natural killer (NK) cells for prophylaxis and treatment of relapse, infections, and graft rejection in both lab studies and prospective clinical trials.  As part of my co-Investigator role of our laboratory, I am interested in understanding NK cell signaling pathways and effector functions.  We are currently designing novel NK cell chimeric antigen receptors to treat high-risk leukemia.  

    Other Interests:  Hiking, mountain climbing, and Yoga.

    Email: mthakar@mcw.edu

    Tyce Kearl, MD, PhD
    Clinical Fellow, Pediatric Hematology/Oncology

    As a physician scientist specializing in pediatric oncology, I am focused on improving the treatment of childhood cancers.  Recent advances in the field of immunotherapy have been exciting, and we are working hard to bring these therapies to our patients.  In order to best utilize immunotherapy for cancer, we still need to answer some basic questions.  Why do immunotherapies work for some patients and not others?  What are the short and long-term risks?  How can we mitigate these risks?  My current research is focused on better understanding cytokine release syndrome (CRS), a serious toxicity of immunotherapies such as monoclonal antibody therapy and chimeric antigen receptor (CAR) T cell therapy.  Our lab has delineated divergent signaling pathways downstream of NK and T cell receptors that lead to cytotoxic effector functions or cytokine production. We are working to leverage this divergent signaling and develop CAR products with less CRS potential while maintaining robust anti-tumor cytotoxicity.  

    Other Interests: Taking my kids backpacking or mountain biking, woodworking, soccer, and tennis

    Email: tkearl@mcw.edu; TKearl@Versiti.org

    Arash Nanbakhsh, DVM, PhD
    Postdoctoral Fellow

    Research Interests: I am a native of Uremia, Iran. After my graduation from veterinary medicine, I moved to Paris, France to get my PhD in immunology from the university of Paris-sud under supervision of Dr. Jean-Henri Bourhis and Dr. Salem Chouaib. Then, I moved to the USA for my postdoctoral fellowship. I like to understand how we can manipulate immune effector T cells and NK cells in order to make them more competent against cancer cell development in translational studies. Additionally, I like to learn more about the basic molecular mechanisms of immune cells signaling pathways. Therefore, I am studying the different signaling pathways modifying T cells activity in ADAP/Fyn knockout mice. Additionally, I would like to understand how microRNAs can regulate NK cells function and development. Another project of mine is to modify NK cells cytotoxic activity against leukemic patients through transduction of the next generation of CAR to reduce cytokine release syndrome (CRS) in cancer patients treated with CAR immunotherapy.

    Other interests: Biking, swimming, mountain climbing, collecting insects and watching soccer, tennis and movies.

    Email: ANanbakhsh@Versiti.org

    Jason Siebert, PhD
    Postdoctoral Fellow

    Research Interest:  I am interested in signaling pathways that regulate the production of inflammatory cytokines and anti-tumor cytotoxic responses of Natural Killer cells.  In particular, my study will focus how to engineer when chimeric antigen receptors that can be introduced into mouse and human Natural Killer cells.  I am currently finishing my course and clinical requirements and will be starting the laboratory work in few months time.  

    Other Interests:  In my free time I like to snowboard and go to concerts.

    Email: jsiebert@mcw.edu

    Shunhua Lao
    Research Technologist

    Email: SLao@Versiti.org

    Dandan Wang
    Graduate Student

    Email: dwang2@Versiti.org

    Ao Mei
    Graduate Student

    Email: amei@versiti.org

    Elaheh Hashemi
    Graduate Student

    Email: ehashemi@versiti.org

  • Publications
    1. MicroRNA Mirc11 optimizes the inflammatory responses by silencing ubiquitin modifiers and altering K63 and K48 ubiquitylation of TRAF6 (2019). Nanbakhsh A, Shirng-Wern, Flister M, Thakar MS, and Malarkannan S. Cancer Immunology Research (In Press).
    2. Method to quantify in vivo cytotoxic potentials of NK cells using donor-derived splenocytes (2019). Schloemer NJ, Abel AM, Thakar MS, Malarkannan S. Methods in Molecular Biology (In Press).
    3. Method to transduce NK cells with lentiviruses (2019). Nanbakhsh A and Malarkannan S. Methods in Molecular Biology (In Press)
    4. Immune checkpoint VISTA controls TLR-mediated anti-tumor immunity via regulating TRAF6 protein turnover and activation in myeloid cells. Xu W, Zheng Y, Zhou J, Yuan Y, Rajasekaran K, Miller H, Olson M, Dong J, Ernstoff MS, Wang D, Malarkannan S, Wang L (2019) Cancer Immunology Research (In Press).
    5. IL-27 regulates NK cell effector functions via MafF-Nrf2 pathway during influenza infection. Kumar P, Rajasekaran K, Thakar M, and Malarkannan S. (2019). Scientific Reports 9(1):4984. doi: 10.1038/s41598-019-41478-6. PMCID: PMC6428861
    6. NK cells: Development, Maturation, and Clinical Utilization. Abel AM, Yang C, Thakar MS, Malarkannan S (2018). Frontiers in ImmunologyFrontiers in Immunology. Aug 13;9:1869. https://doi.org/10.3389/fimmu.2018.01869. PMCID: PMC6099181 
    7. IQGAP1 regulates cytoskeletal reorganization and facilitates NKG2D-mediated mTORC1 activation and cytokine gene translation in NK cells. Abel A, Yang C, Gerbec Z, Shirng-Wern, Flister M, Thakar MS, Malarkannan S. (2018) Frontiers in Immunology. doi.org/10.3389/fimmu.2018.01168. 
    8. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Xu W, Hiếu T, Malarkannan S, Wang L. (2018) Cell Mol Immunol. doi:10.1038/cmi.2017.148. PMID:29375120.
    9. mTORC1 and mTORC2 differentially regulate NK cell development. Yang C, Thakar M, and Malarkannan S (2018) eLife. doi: 10.7554/eLife.35619. PMID:29809146.
    10. Diacylglyerol kinase ζ and Casitas b-lineage proto-oncogene b deficient mice have similar functional outcomes in T cells but DGKζ-deficient mice have increased T cell activation and tumor clearance. Wesley E, Malarkannan S, and M Riese. (2018). ImmunoHorizons 2 (4) 107-118. DOI: https://doi.org/10.4049/immunohorizons.1700055.
    11. Cutting Edge: Check Your Mice-A Point Mutation in the Ncr1 Locus Identified in CD45.1 Congenic Mice with Consequences in Mouse Susceptibility to Infection (2018). Jang Y, Gerbec ZJ, Won T, Choi B, Podsiad A, Moore BB, Malarkannan S, Laouar Y. J Immunol DOI:10.4049.
    12. Dextran enhances lentiviral transduction efficiency of murine and human primary NK cells. Nanbakhsh A, Best B, Riese M, Rao S, Wang L, Medin J, Thakar MS, and Malarkannan S. (2018). Journal of Experimental Visualization. doi: 10.3791/55063. PMID: 29364266.
    13. Immune-checkpoint protein VISTA regulates the IL-23/IL-17 inflammatory axis by suppressing the responses of myeloid and T cells. Li N, Xu W, Yuan Y, Ayithan N, Imai Y, Wu X, Miller H, Olson M, Turk MJ, Hwang ST, Malarkannan S, Wang L (2017) Scientific Reports, 7, 1485. PMID: 28469254
    14. Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy. Rajasekaran K, Riese MJ, Rao S, Wang L, Thakar MS, Sentman CL, and Malarkannan S. Front Immunol. 2016 May 12;7:176. doi: 10.3389/fimmu.2016.00176. eCollection 2016 PMID: 27242783
    15. The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA9Fisher J, Peterson J, Reimer M, Stelloh C, Pulakanti K, Gerbec JC, Abel AM, Miksanek J, McNulty M, Malarkannan S, Crispino J, Milanovich S, and Rao S (2016). Leukemia. 3, 712-719 PMID: 27242783. 
    16. The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells. Gerbec ZJ, Thakar MS, Malarkannan S. Front Immunol. 2015 Sep 16;6:472. doi: 10.3389/fimmu.2015.00472. eCollection 2015. Review. PMID:26441977
    17. TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β. Arumugam V, Blumen T, Wesley E, Schmidt AM, Kambayashi T, Malarkannan S, Riese MJ. J Leukoc Biol. 2015 Nov;98(5):703-12. doi: 10.1189/jlb.2HIMA1214-578R. Epub 2015 Jul 7. PMID:26153417
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