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Stephanie K. Dougan, PhD


Researcher


Researcher

  • Assistant Professor in Microbiology and Immunobiology, Division of Immunology, Harvard Medical School

Contact Information

  • Office Phone Number617-582-9609

Bio

Stephanie Dougan received her PhD in immunology from Harvard University in 2007 after studying NKT cells and CD1d antigen presentation with Dr. Richard Blumberg. She then performed postdoctoral work at the Whitehead Institute with Dr. Hidde Ploegh. While at Whitehead, she collaborated with Dr. Rudolf Jaenisch to learn somatic cell nuclear transfer and generate a panel of transnuclear mice. Stephanie Dougan joined the DFCI and Harvard faculty in 2014.

Recent Awards:

  • Pathway to Leadership Award, Pancreatic Cancer Action Network and the American Association of Cancer Research 2012-2017

Research

Preclinical models for immunotherapy, including transnuclear and CRISPR gene-modified mice

Somatic cell nuclear transfer (SCNT) may be used to clone mice from lymphocytes of defined specificity. By harvesting as few as 200 primary lymphocytes from animals that are at the peak of an immune response, and by transfer of the nucleus from such antigen specific lymphocytes into an enucleated oocyte, embryonic stem cells that harbor the genetic rearrangements encoding the original antigen receptor may be obtained and used for the construction of transnuclear mice.

These animals contain T or B cells of the appropriate specificity, have no genetic alterations other than the physiological TCR/BCR rearrangements, and are the closest approximation of physiological immune responses to date. Importantly, the generation of transnuclear mice is rapid, requiring approximately 6 weeks from T cell harvest to obtaining chimeric animals. Like TCR and BCR transgenics, transnuclear mice are broadly useful for addressing diverse questions. The Dougan lab generates transnuclear mouse models to explore questions of anti-tumor immunity.

Our long term goal is to understand the complex network of cellular interactions that shape the tumor microenvironment. CD8 T cells do not occur in isolation; they operate in oligoclonal fashion amid regulatory T cells, myeloid cells, and other immune infiltrates, not to mention heterogeneous tumor cells, stroma, and vasculature. These interactions cannot be accurately modeled using xenografts, nor are they fully replicated in humanized mice that develop human leukocytes, but still face cross-species barriers with respect to immune-stromal interactions and T cell development.

The Dougan lab clones mice from a variety of tumor-infiltrating lymphocytes in order to study the effects of each lymphocyte type in isolation, and more importantly, when combined with each other and with various immune-based therapies. We also use the technology in reverse to clone mice from tumor-infiltrating Tregs as a means of determining their antigen-specificity.

Currently the lab focuses on three major tumor types: melanoma, sarcoma, and pancreatic cancer. Of these, pancreatic cancer has been the most refractory to immunotherapy. We are using a combination of RNAseq profiling and targeted gene silencing in pancreatic-tumor specific CD8 T cells to design effective immunotherapies for pancreatic cancer.

Heckler M, Dougan SK. Unmasking Pancreatic Cancer: Epitope Spreading After Single Antigen Chimeric Antigen Receptor T-Cell Therapy in a Human Phase I Trial. Gastroenterology. 2018 Jul; 155(1):11-14.
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Dougan SK, Dougan M. Regulation of innate and adaptive antitumor immunity by IAP antagonists. Immunotherapy. 2018 May 29.
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Krall JA, Reinhardt F, Mercury OA, Pattabiraman DR, Brooks MW, Dougan M, Lambert AW, Bierie B, Ploegh HL, Dougan SK, Weinberg RA. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med. 2018 Apr 11; 10(436).
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Ingram JR, Blomberg OS, Rashidian M, Ali L, Garforth S, Fedorov E, Fedorov AA, Bonanno JB, Le Gall C, Crowley S, Espinosa C, Biary T, Keliher EJ, Weissleder R, Almo SC, Dougan SK, Ploegh HL, Dougan M. Anti-CTLA-4 therapy requires an Fc domain for efficacy. Proc Natl Acad Sci U S A. 2018 Apr 10; 115(15):3912-3917.
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Dougan M, Ingram JR, Jeong HJ, Mosaheb MM, Bruck PT, Ali L, Pishesha N, Blomberg O, Tyler PM, Servos MM, Rashidian M, Nguyen QD, von Andrian UH, Ploegh HL, Dougan SK. Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs. Cancer Immunol Res. 2018 Apr; 6(4):389-401.
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Jeong HJ, Abhiraman GC, Story CM, Ingram JR, Dougan SK. Generation of Ca2+-independent sortase A mutants with enhanced activity for protein and cell surface labeling. PLoS One. 2017; 12(12):e0189068.
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Clancy-Thompson E, Ali L, Bruck PT, Exley MA, Blumberg RS, Dranoff G, Dougan M, Dougan SK. IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells. Cancer Immunol Res. 2018 Jan; 6(1):25-35.
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Dougan SK. The Pancreatic Cancer Microenvironment. Cancer J. 2017 Nov/Dec; 23(6):321-325.
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Ingram JR, Dougan M, Rashidian M, Knoll M, Keliher EJ, Garrett S, Garforth S, Blomberg OS, Espinosa C, Bhan A, Almo SC, Weissleder R, Lodish H, Dougan SK, Ploegh HL. PD-L1 is an activation-independent marker of brown adipocytes. Nat Commun. 2017 09 21; 8(1):647.
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Zeissig S, Peuker K, Iyer S, Gensollen T, Dougan SK, Olszak T, Kaser A, Blumberg RS. CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc Natl Acad Sci U S A. 2017 09 26; 114(39):10449-10454.
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Ingram JR, Blomberg OS, Sockolosky JT, Ali L, Schmidt FI, Pishesha N, Espinosa C, Dougan SK, Garcia KC, Ploegh HL, Dougan M. Localized CD47 blockade enhances immunotherapy for murine melanoma. Proc Natl Acad Sci U S A. 2017 09 19; 114(38):10184-10189.
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Clancy-Thompson E, Chen GZ, Tyler PM, Servos MM, Barisa M, Brennan PJ, Ploegh HL, Dougan SK. Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets. J Immunol. 2017 07 01; 199(1):159-171.
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Dougan M, Dougan SK. Targeting Immunotherapy to the Tumor Microenvironment. J Cell Biochem. 2017 10; 118(10):3049-3054.
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Pishesha N, Bilate AM, Wibowo MC, Huang NJ, Li Z, Deshycka R, Bousbaine D, Li H, Patterson HC, Dougan SK, Maruyama T, Lodish HF, Ploegh HL. Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease. Proc Natl Acad Sci U S A. 2017 03 21; 114(12):3157-3162.
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Tyler PM, Servos MM, de Vries RC, Klebanov B, Kashyap T, Sacham S, Landesman Y, Dougan M, Dougan SK. Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy. Mol Cancer Ther. 2017 Mar; 16(3):428-439.
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Sanderson NS, Zimmermann M, Eilinger L, Gubser C, Schaeren-Wiemers N, Lindberg RL, Dougan SK, Ploegh HL, Kappos L, Derfuss T. Cocapture of cognate and bystander antigens can activate autoreactive B cells. Proc Natl Acad Sci U S A. 2017 01 24; 114(4):734-739.
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Bilate AM, Bousbaine D, Mesin L, Agudelo M, Leube J, Kratzert A, Dougan SK, Victora GD, Ploegh HL. Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol. 2016 Aug 26; 1(2):eaaf7471.
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Sanecka A, Yoshida N, Dougan SK, Jackson J, Shastri N, Ploegh H, Blanchard N, Frickel EM. Transnuclear CD8 T cells specific for the immunodominant epitope Gra6 lower acute-phase Toxoplasma gondii burden. Immunology. 2016 Nov; 149(3):270-279.
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Dura B, Servos MM, Barry RM, Ploegh HL, Dougan SK, Voldman J. Longitudinal multiparameter assay of lymphocyte interactions from onset by microfluidic cell pairing and culture. Proc Natl Acad Sci U S A. 2016 06 28; 113(26):E3599-608.
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Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, Dougan SK, Petersen BS, Melum E, Pertel T, Clayton KL, Raab M, Chen Q, Beauchemin N, Yazaki PJ, Pyzik M, Ostrowski MA, Glickman JN, Rudd CE, Ploegh HL, Franke A, Petsko GA, Kuchroo VK, Blumberg RS. Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2016 08 18; 536(7616):359.
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Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Corrigendum: Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2016 Feb; 34(2):210.
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Tafesse FG, Rashidfarrokhi A, Schmidt FI, Freinkman E, Dougan S, Dougan M, Esteban A, Maruyama T, Strijbis K, Ploegh HL. Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. PLoS Pathog. 2015 Oct; 11(10):e1005188.
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Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2015 May; 33(5):538-42.
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Dura B, Dougan SK, Barisa M, Hoehl MM, Lo CT, Ploegh HL, Voldman J. Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing. Nat Commun. 2015 Jan 13; 6:5940.
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Santone M, Aprea S, Wu TY, Cooke MP, Mbow ML, Valiante NM, Rush JS, Dougan S, Avalos A, Ploegh H, De Gregorio E, Buonsanti C, D'Oro U. A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells. Hum Vaccin Immunother. 2015; 11(8):2038-50.
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Strijbis K, Yilmaz OH, Dougan SK, Esteban A, Gröne A, Kumamoto CA, Ploegh HL. Intestinal colonization by Candida albicans alters inflammatory responses in Bruton's tyrosine kinase-deficient mice. PLoS One. 2014; 9(11):e112472.
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Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK, Laerdahl JK, Stade B, Forster M, Schreiber S, Weir D, Leichtner AM, Franke A, Blumberg RS. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut. 2015 Dec; 64(12):1889-97.
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Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, Dougan SK, Petersen BS, Melum E, Pertel T, Clayton KL, Raab M, Chen Q, Beauchemin N, Yazaki PJ, Pyzik M, Ostrowski MA, Glickman JN, Rudd CE, Ploegh HL, Franke A, Petsko GA, Kuchroo VK, Blumberg RS. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015 01 15; 517(7534):386-90.
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Shi J, Kundrat L, Pishesha N, Bilate A, Theile C, Maruyama T, Dougan SK, Ploegh HL, Lodish HF. Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes. Proc Natl Acad Sci U S A. 2014 Jul 15; 111(28):10131-6.
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Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, Brogdon J, Lamb J, Turley SJ, Ploegh HL, Root DE, Love JC, Dranoff G, Hacohen N, Cantor H, Wucherpfennig KW. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature. 2014 Feb 06; 506(7486):52-7.
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Dougan SK, Ashour J, Karssemeijer RA, Popp MW, Avalos AM, Barisa M, Altenburg AF, Ingram JR, Cragnolini JJ, Guo C, Alt FW, Jaenisch R, Ploegh HL. Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus. Nature. 2013 Nov 21; 503(7476):406-9.
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Dougan SK, Dougan M, Kim J, Turner JA, Ogata S, Cho HI, Jaenisch R, Celis E, Ploegh HL. Transnuclear TRP1-specific CD8 T cells with high or low affinity TCRs show equivalent antitumor activity. Cancer Immunol Res. 2013 Aug; 1(2):99-111.
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Fang M, Xie H, Dougan SK, Ploegh H, van Oudenaarden A. Stochastic cytokine expression induces mixed T helper cell States. PLoS Biol. 2013 Jul; 11(7):e1001618.
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Strijbis K, Tafesse FG, Fairn GD, Witte MD, Dougan SK, Watson N, Spooner E, Esteban A, Vyas VK, Fink GR, Grinstein S, Ploegh HL. Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages. PLoS Pathog. 2013; 9(6):e1003446.
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Dougan SK, Ogata S, Hu CC, Grotenbreg GM, Guillen E, Jaenisch R, Ploegh HL. IgG1+ ovalbumin-specific B-cell transnuclear mice show class switch recombination in rare allelically included B cells. Proc Natl Acad Sci U S A. 2012 Aug 21; 109(34):13739-44.
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Witte MD, Cragnolini JJ, Dougan SK, Yoder NC, Popp MW, Ploegh HL. Preparation of unnatural N-to-N and C-to-C protein fusions. Proc Natl Acad Sci U S A. 2012 Jul 24; 109(30):11993-8.
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Hess GT, Cragnolini JJ, Popp MW, Allen MA, Dougan SK, Spooner E, Ploegh HL, Belcher AM, Guimaraes CP. M13 bacteriophage display framework that allows sortase-mediated modification of surface-accessible phage proteins. Bioconjug Chem. 2012 Jul 18; 23(7):1478-87.
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Popp MW, Dougan SK, Chuang TY, Spooner E, Ploegh HL. Sortase-catalyzed transformations that improve the properties of cytokines. Proc Natl Acad Sci U S A. 2011 Feb 22; 108(8):3169-74.
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Dougan SK, Hu CC, Paquet ME, Greenblatt MB, Kim J, Lilley BN, Watson N, Ploegh HL. Derlin-2-deficient mice reveal an essential role for protein dislocation in chondrocytes. Mol Cell Biol. 2011 Mar; 31(6):1145-59.
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Dougan M, Dougan S, Slisz J, Firestone B, Vanneman M, Draganov D, Goyal G, Li W, Neuberg D, Blumberg R, Hacohen N, Porter D, Zawel L, Dranoff G. IAP inhibitors enhance co-stimulation to promote tumor immunity. J Exp Med. 2010 Sep 27; 207(10):2195-206.
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Zeissig S, Dougan SK, Barral DC, Junker Y, Chen Z, Kaser A, Ho M, Mandel H, McIntyre A, Kennedy SM, Painter GF, Veerapen N, Besra GS, Cerundolo V, Yue S, Beladi S, Behar SM, Chen X, Gumperz JE, Breckpot K, Raper A, Baer A, Exley MA, Hegele RA, Cuchel M, Rader DJ, Davidson NO, Blumberg RS. Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. J Clin Invest. 2010 Aug; 120(8):2889-99.
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Hu CC, Dougan SK, Winter SV, Paton AW, Paton JC, Ploegh HL. Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes. J Exp Med. 2009 Oct 26; 206(11):2429-40.
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McGehee AM, Dougan SK, Klemm EJ, Shui G, Park B, Kim YM, Watson N, Wenk MR, Ploegh HL, Hu CC. XBP-1-deficient plasmablasts show normal protein folding but altered glycosylation and lipid synthesis. J Immunol. 2009 Sep 15; 183(6):3690-9.
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Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL. XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells. EMBO J. 2009 Jun 03; 28(11):1624-36.
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Kaser A, Hava DL, Dougan SK, Chen Z, Zeissig S, Brenner MB, Blumberg RS. Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group 1 CD1 molecules. Eur J Immunol. 2008 Aug; 38(8):2351-9.
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Hussain MM, Rava P, Pan X, Dai K, Dougan SK, Iqbal J, Lazare F, Khatun I. Microsomal triglyceride transfer protein in plasma and cellular lipid metabolism. Curr Opin Lipidol. 2008 Jun; 19(3):277-84.
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Zeissig S, Kaser A, Dougan SK, Nieuwenhuis EE, Blumberg RS. Role of NKT cells in the digestive system. III. Role of NKT cells in intestinal immunity. Am J Physiol Gastrointest Liver Physiol. 2007 Dec; 293(6):G1101-5.
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Dougan SK, Rava P, Hussain MM, Blumberg RS. MTP regulated by an alternate promoter is essential for NKT cell development. J Exp Med. 2007 Mar 19; 204(3):533-45.
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Dougan SK, Kaser A, Blumberg RS. CD1 expression on antigen-presenting cells. Curr Top Microbiol Immunol. 2007; 314:113-41.
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Dougan SK, Salas A, Rava P, Agyemang A, Kaser A, Morrison J, Khurana A, Kronenberg M, Johnson C, Exley M, Hussain MM, Blumberg RS. Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells. J Exp Med. 2005 Aug 15; 202(4):529-39.
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Chan WH, Zerizer I, Shergill N, Shergill I, Dougan S. A rare cause of abdominal pain. Gut. 2004 Sep; 53(9):1261, 1266.
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Dougan S, DiNardo S. Drosophila wingless generates cell type diversity among engrailed expressing cells. Nature. 1992 Nov 26; 360(6402):347-50.
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