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Matthew Riese, MD, PhD

Matthew Riese, MD, PhD

Associate Investigator

Associate Professor
Department of Medicine
Division of Hematology/Oncology
Medical College of Wisconsin

Education and training

Doctoral Training
M.D. and Ph.D., Medical College of Wisconsin

Internship and Residency
Brigham and Women's Hospital/Harvard Medical School

Hematology/Oncology Fellowship and 
Post-doctoral Research

University of Pennsylvania

Contact Us

Matthew Riese, MD, PhD

Associate Investigator
(414) 937-6805 Fax: (414) 937-6284

  • Research Interests

    Immunobiology

    Research in the Riese lab focuses on understanding how T cells are affected by the tumor microenvironment, and how they can be manipulated to overcome the inhibitory mediators present within that environment. 

    One means to enhance T cell responses is to target negative modulators of signal transduction downstream from the T cell receptor (TCR). Perhaps the most important signaling event downstream of the TCR is the cleavage of the phosphoinositide PIP2 into the second messengers diacylglycerol (DAG) and IP3. Whereas IP3 mobilizes Calcium flux from the endoplasmic reticulum, DAG binds and activates additional proteins important in signal transduction, such as the Ras activating protein RasGRP1. DAG-mediated signaling is terminated by diacylglycerol kinases (dgk’s), which phosphorylate DAG to form phosphatidic acid. It has been appreciated for some time that inhibition of dgk’s results in enhanced TCR signal transduction and imparts enhanced function to T cells. We have found that T cells deficient in dgk’s generate enhanced anti-tumor responses in a variety of murine models. A major focus of the lab is to dissect the molecular underpinnings of how dgk’s function to limit anti-tumor responses. 

    Chimeric antigen receptors (CARs) represent an emerging strategy for generating T cell responses against tumors. CARs are fusion proteins that contain an extracellular antibody domain specific for a given tumor antigen linked to an intracellular T cell signaling component, such as CD3ζ. CD8+ T cells can be engineered to express CARs such that contact with tumor cells and their cognate antigens results in T cell activation and cytolysis of tumor cells. A second major focus of the lab is in understanding how CARs utilize TCR machinery to transduce signals and how these signals can be optimized to enhance tumor cell lysis.

    TGFβ is a potent inhibitor of CD8+ T cell responses within the tumor microenvironment making it attractive as a target to enhance T cell immunotherapies in cancer. However, effective targeting of TGFβ results in significant effects in other tissues, such as the myocardium, where TGFβ is known to play an important role. Further, total inactivation of TGFβ in T cells results in profound auto-immunity. We have identified a novel non-Smad-based signaling pathway in T cells that involves the cell adhesion molecule PECAM-1. Disruption of this pathway attenuates TGFβ-mediated inhibition of CD8+ T cell functional responses, but does not induce overt auto-immune disease. Further, PECAM-1 expression is limited to cells of hematopoietic lineage or the endothelium, reducing potential off-tumor effects in targeting this interaction. Further work in the lab seeks to identify the mechanistic basis of the TGFβ-PECAM-1 signaling axis.

  • Grant Support
    • American Cancer Society Pilot Research Grant, "Targeting diacylglycerol kinases toward enhancing anti-tumor responses in vivo in CAR-transduced T cells" (2013)
    • Central Society for Clinical Research - Early Career Development Award (2013-2014)
    • NIH K08 CA151893. "Effects of diacylglycerol kinase zeta deficiency on CD8+ T cell function" (10/2010 - 09/2015)
    • American Society for Hematology Bridge Grant Award. Title: Exploiting a Novel TGFβ-PECAM-1 Inhibitory Axis to Augment T Cell Anti-tumor Activity. 3/1/2016-2/27/2017.
  • Lab

    Sandra Holzhauer
    Research Technologist

    Poojitha Sitaram
    Research Scientist

  • Publications
    • Bajor DL, Mick R, Riese MJ, Huang AC, Sullivan B, Richman LP, Torigan DA, George SM, Stelekati E, Chen F, Melenhorst JJ, Lacey SF, Xu X, Wherry EJ, Gangadhar TC, Amaravadi RK, Schuchter LM, and Vonderheide RH. “Clinical response and immune anctivation with CD40 agonism and CTLA-4 blockade in patients with metastatic melanoma.” OncoImmunology. 2018 Aug 20; 7(10).
    • Newman DK, Fu G, McOlash L, Schauder D, Newman PJ, Johnson BD, Gershan JA, Cui W, Rao S, Riese MJ. “PECAM-1 expression on CD8+ T cells differs from CD4+ T cells and includes memory subsets.” Journal of Leukocyte Biology. 2018 Jul 31. (Frontline Science designation, accompanied by dedicated editorial in journal).
    • Wesley E, Xin G, McAllister D, Malarkannan S, Newman DK, Dwinell MB, Johnson BD, Cui W, Riese MJ. “Diacylglycerol kinase z (DGKz) and Casitas b-Lineage Proto-oncogene (Cbl-b) deficient mice have similar outcomes in T cells but DGKz-deficient mice have increased T cell activation and tumor clearance.” ImmunoHorizons. 2018 Apr 1;2(4):107-118.
    • Nanbakhsh A, Best B, Riese M, Rao S, Wang L, Medin J, Thakar MS, Malarkannan S. “Dextran enhances the transduction efficiency of murine and human primary NK cells.” Journal of Visualized Experiments. 2018 Jan 15;(131).
    • Jing W, Gershan JA, Hozhauer S, Weber J, Palen K, McOlash L, Pulakanti K, Wesley E, Rao S, Johnson BD, Riese MJ. “T cells deficient iin diacylglycerol kinase-z are resistant to PD-1 inhibition and help create persistent host immunity to leukemia.” Cancer Research. 2017 Oct 15;77(20):5676-5686.
    • Jing W, Gershan JA, Blitzer GC, Palen K, Weber J, McOlash L, Riese M, Johnson, BD. “Adoptive Cell Therapy using PD-1+ myeloma-reactive T cells eliminates established myeloma in mice.” Journal for ImmunoTherapy of Cancer. 2017 Jun 20;5:51.
    • Raychaudhuri R, Riese MJ, Bylow K, Burfeind J, Mackinnon AC, Tolat PP, Iczkowski KA, Kilari D. “Immune check point inhibition in sarcomatoid renal cell carcinoma: a new treatment paradigm.” Clinical Genitourinary Cancer. 2017 May 25. 7673(17)30155-6.
    • Frankel AE, Flaherty KT, Weiner GJ, Chen R, Azad NS, Pishvaian MJ, Thompson JA, Taylor MH, Mahadevan D, Lockhart AC, Vaishampayan UN, Berlin JD, Smith DC, Sarantopoulos J, Riese M, Saleh MN, Ahn C, Frenkel EP. “Academic Cancer Center Phase I Program Development.” Oncologist. 2017 Apr;22(4):369-74.
    • Riese MJ, Moon EK, Johnson BD, and Albelda SM. “Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer.” Frontiers in Cell and Developmental Biology. 2016 Oct 17; 4:108.
    • Rajasekaran K, Riese MJ, Rao S, Wang L, Thakar MS, Sentman CL, Malarkannan S. “Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy.” Frontiers in Immunology. 2016 Apr; 7(176).
    • Newman DK, Adams T, Fu G, Cui W, Arumugam V, Riese MJ. “The adhesion molecule PECAM-1 enhances the TGF-β-mediated inhibition of T cell function.” Science Signaling. 2016 Mar 8; 9(418):ra27.
    • Arumugam V, Bluemn T, Wesley E, Schmidt AM, Kambayashi T, Malarkannan S, Riese MJ. “TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β.” Journal of Leukocyte Biology. 2015 Nov; 98(5):703-12.
    • Abel, AM, Schuldt KM, Rajasekaran K, Hwang D, Riese MJ, Rao S, Thakar MS, and Malarkannan S. “IQGAP1: Insights into the function of a molecular puppeteer.” Molecular Immunology. 2015 Jun; 65(2):336-49.
    • Schmidt AM, Lu W, Huang Y, Burkhardt JK, Riese MJ, Maltzman JS, Jordan MS, Kambayashi T. "TCR signaling modulates the suppressive function of regulatory T cells." Journal of Immunology. 2015 May 1; 194(9).
    • Min SH, Suzuki A, Stalker TJ, Guzman JF, Zhao L, Lian L, Riese MJ, Joshi R, Meng R, Koretzky G, Marks MS, Choi JK, Abrams CS.  "Loss of PIKFyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice." Nature Communications. 2014 Sep 2; 5:4691.
    • Wang LC, Riese MJ, Moon EK, Albelda SM.  "Overcoming intrinsic inhibitory pathways to augment the function of adoptively transferred T cells for cancer: Re-tuning your CAR before hitting a rocky road."  Oncoimmunology. 2013 Oct 10; e26492-93.
    • Joshi RP, Schmidt A, Das J, Pytel D, Riese MJ, Lester M, Diehl JA, Behrens EM, Kambayashi T, Koretzky GA.  "A predominant role for the zeta isoform of diacylgltcerol kinase in regulatory T cell development and TCR-mediated Ras signaling." Science Signaling. 2013 Nov 25; (303).
    • Riese MJ, Wang LC, Moon EK, Ranganathan A, Joshi RP, June CH, Koretzky GA, Albelda SM.  "Enhanced effector responses in activated CD8+ T Cells deficient in diaclyglycerol kinases."  Cancer Research. 2013 Jun 15. 73(12):3566-77.
    • Bobrovnikova-Marjon E, Pytel D, Riese MJ, Vaites LP, Singh N, Koretzky GA, Witze ES, Diehl JA, “PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation.” Molecular and Cellular Biology. 2012 Jun;32(12); 2268-78.
    • Wu GF, Corbo E, Schmidt M, Smith-Garvin JE, Riese MJ, Jordan MS, Laufer TM, Brown EJ, Maltzman JS. “Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses.” European Journal of Immunology. 2011 Apr 6. 2064-73.
    • Riese MJ, Grewal J, Das J, Zou T, Patil V, Chakraborty AK, Koretzky GA. “Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses.” Journal of Biological Chemistry. 2011 Feb; 286(7); 5254-65.
    • Riese MJ, Vaughn DJ. "Chemistry for patients with poor prognosis germ cell tumors." World Journal of Urology, 2009 Aug; 27(4):471-6.
    • Janzen V, Fleming HE, Riedt T, Karlsson G, Riese MJ, Lo Celso C, Reynolds G, Milne CD, Paige CJ, Karlsson S, Woo M, Scadden DT. "Stem cell responsiveness to exogenous signals limited by Caspase-3." Cell Stem Cell. 2008 Jun; 5;2(6): 584-94.
    • Maresso AW, Riese MJ, Barbieri JT. “Molecular heterogeneity of a type-III cytotoxin, Pseudomonas aeruginosa Exoenzyme S.” Biochemistry. 2003 Dec 9; 42(48): 14249-57.
    • Pederson KJ, Krall R, Riese MJ, Barbieri JT. “Intracellular localization modulates targeting of ExoS, a type-III cytotoxin, to eukaryotic signaling proteins.” Molecular Microbiology. 2002 Dec; 46 (5): 1381-90.
    • Barbieri JT, Riese MJ, Aktories K. “Bacterial toxins that modify the actin cytoskeleton.” Annual Reviews of Cell and Developmental Biology. 2002; 18: 315-44.
    • Fraylick JE, Riese MJ, Vincent TS, Barbieri JT, Olson JC. “ADP-ribosylation and functional effects of Pseudomonas Exoenzyme S on cellular RalA.” Biochemistry. 2002 Jul 30; 41 (30): 9680-87.
    • Riese MJ, Barbieri JT. “Membrane localization contributes to the in vivo ADP-ribosylation of Ras by Pseudomonas aeruginosa ExoS.” Infection and Immunity. 2002 Apr; 70 (4): 2230-32.
    • Riese MJ, Goehring UM, Ehrmantraut ME, Moss J, Barbieri JT, Aktories K, Schmidt G. “Auto-ADP-ribosylation of Pseudomonas aeruginosa ExoS.” Journal of Biological Chemistry. 2002 Apr 5; 277 (14): 12082-88.
    • Riese MJ, Wittinghofer A, Barbieri JT. “ADP-ribosylation of Arg-41 of Rap by ExoS inhibits the ability of Rap to interact with its guanine nucleotide exchange factor, C3G.” Biochemistry. 2001 Mar 20; 40 (11): 3289-94.
    • Chen Y, Riese MJ, Killinger MA, Hoffmann, FM. “A genetic screen for modifiers of Drosophila decapentaplegic signaling identifies mutations in punt, Mothers against dpp, and the BMP-7 homologue, 60A.” Development. 1998 May; 125 (9): 1759-68.
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