Subramaniam Malarkannan, PhD
Professor and Gardetto Chair for Immunology and Immunotherapy; Professor, Medicine (Hematology and Oncology) and Microbiology & Immunology; Senior Investigator, Versiti Blood Research Institute
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.
(Yang C, Siebert JR, Burns R, Zheng Y, Mei A, Bonacci B, Wang D, Urrutia RA, Riese MJ, Rao S, Carlson KS, Thakar MS, Malarkannan S.) Elife. 2020 May 14;9 PMID: 32406817 PMCID: PMC7255804 SCOPUS ID: 2-s2.0-85085630468 05/15/2020
(Nanbakhsh A, Malarkannan S.) Methods Mol Biol. 2020;2097:107-113 PMID: 31776922 SCOPUS ID: 2-s2.0-85075740556 11/30/2019
(Schloemer NJ, Abel AM, Thakar MS, Malarkannan S.) Methods Mol Biol. 2020;2097:115-123 PMID: 31776923 SCOPUS ID: 2-s2.0-85075755837 11/30/2019
(Chen Y, Yang M, Huang W, Chen W, Zhao Y, Schulte ML, Volberding P, Gerbec Z, Zimmermann MT, Zeighami A, Demos W, Zhang J, Knaack DA, Smith BC, Cui W, Malarkannan S, Sodhi K, Shapiro JI, Xie Z, Sahoo D, Silverstein RL.) Circ Res. 2019 12 06;125(12):1087-1102 PMID: 31625810 PMCID: PMC6921463 SCOPUS ID: 2-s2.0-85076330129 10/19/2019
(Sitaram P, Uyemura B, Malarkannan S, Riese MJ.) Int J Mol Sci. 2019 Nov 20;20(23) PMID: 31756921 PMCID: PMC6929154 SCOPUS ID: 2-s2.0-85075296555 11/24/2019
(Liberio N, Robinson H, Nugent M, Simpson P, Margolis DA, Malarkannan S, Keever-Taylor C, Thakar MS.) Pediatr Blood Cancer. 2019 11;66(11):e27950 PMID: 31368194 PMCID: PMC6754268 SCOPUS ID: 2-s2.0-85070087706 08/02/2019
(Nanbakhsh A, Srinivasamani A, Holzhauer S, Riese MJ, Zheng Y, Wang D, Burns R, Reimer MH, Rao S, Lemke A, Tsaih SW, Flister MJ, Lao S, Dahl R, Thakar MS, Malarkannan S.) Cancer Immunol Res. 2019 10;7(10):1647-1662 PMID: 31515257 SCOPUS ID: 2-s2.0-85072848720 09/14/2019
(Yang C, Siebert JR, Burns R, Gerbec ZJ, Bonacci B, Rymaszewski A, Rau M, Riese MJ, Rao S, Carlson KS, Routes JM, Verbsky JW, Thakar MS, Malarkannan S.) Nat Commun. 2019 09 02;10(1):3931 PMID: 31477722 PMCID: PMC6718415 SCOPUS ID: 2-s2.0-85071610251 09/04/2019
(Xu W, Dong J, Zheng Y, Zhou J, Yuan Y, Ta HM, Miller HE, Olson M, Rajasekaran K, Ernstoff MS, Wang D, Malarkannan S, Wang L.) Cancer Immunol Res. 2019 09;7(9):1497-1510 PMID: 31340983 PMCID: PMC6726548 SCOPUS ID: 2-s2.0-85071783703 07/26/2019
(Reimer M Jr, Pulakanti K, Shi L, Abel A, Liang M, Malarkannan S, Rao S.) BMC Dev Biol. 2019 07 08;19(1):16 PMID: 31286885 PMCID: PMC6615237 SCOPUS ID: 2-s2.0-85068878011 07/10/2019
(Thakar MS, Kearl TJ, Malarkannan S.) Front Oncol. 2019;9:1529 PMID: 32076597 PMCID: PMC7006459 02/23/2020
(Sitaram P, Uyemura B, Malarkannan S, Riese MJ.) International Journal of Molecular Sciences. 1 December 2019;20(23) SCOPUS ID: 2-s2.0-85075296555 12/01/2019