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Stephanie K. Dougan, PhD


Researcher


Researcher

  • Principal Investigator, Cancer Immunology and Virology, Dana-Farber Cancer Institute
  • Assistant Professor 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.

Understanding and treating the inflammatory adverse events of cancer immunotherapy. Cell. 2021 Mar 18; 184(6):1575-1588.
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TGFß: Protecting PD-1 from mRNA Decay. Cancer Immunol Res. 2020 12; 8(12):1464.
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Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. Cell. 2020 08 06; 182(3):655-671.e22.
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Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH. Open Biol. 2020 02; 10(2):190235.
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SMAC mimetics throw a molecular switch to control TH17 responses. Sci Signal. 2019 08 27; 12(596).
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Programmable bacteria as cancer therapy. Nat Med. 2019 07; 25(7):1030-1031.
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Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1. EMBO J. 2019 07 15; 38(14):e101260.
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Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1. EMBO J. 2019 May 31.
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GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation. Immunity. 2019 04 16; 50(4):796-811.
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Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities. Gastroenterology. 2019 05; 156(7):2056-2072.
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Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell-Effector Responses. Cancer Immunol Res. 2018 12; 6(12):1524-1536.
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Radiation and Local Anti-CD40 Generate an Effective in situ Vaccine in Preclinical Models of Pancreatic Cancer. Front Immunol. 2018; 9:2030.
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Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity. J Exp Med. 2018 10 01; 215(10):2617-2635.
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One-step CRISPR/Cas9 method for the rapid generation of human antibody heavy chain knock-in mice. EMBO J. 2018 09 14; 37(18).
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Unmasking Pancreatic Cancer: Epitope Spreading After Single Antigen Chimeric Antigen Receptor T-Cell Therapy in a Human Phase I Trial. Gastroenterology. 2018 07; 155(1):11-14.
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Regulation of innate and adaptive antitumor immunity by IAP antagonists. Immunotherapy. 2018 07; 10(9):787-796.
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The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med. 2018 04 11; 10(436).
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Anti-CTLA-4 therapy requires an Fc domain for efficacy. Proc Natl Acad Sci U S A. 2018 04 10; 115(15):3912-3917.
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Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs. Cancer Immunol Res. 2018 04; 6(4):389-401.
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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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IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells. Cancer Immunol Res. 2018 01; 6(1):25-35.
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The Pancreatic Cancer Microenvironment. Cancer J. 2017 Nov/Dec; 23(6):321-325.
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PD-L1 is an activation-independent marker of brown adipocytes. Nat Commun. 2017 09 21; 8(1):647.
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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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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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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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Targeting Immunotherapy to the Tumor Microenvironment. J Cell Biochem. 2017 10; 118(10):3049-3054.
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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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Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy. . 2017 03; 16(3):428-439.
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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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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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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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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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Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2016 08 18; 536(7616):359.
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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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Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. PLoS Pathog. 2015 Oct; 11(10):e1005188.
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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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Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing. Nat Commun. 2015 Jan 13; 6:5940.
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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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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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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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CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015 01 15; 517(7534):386-90.
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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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In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature. 2014 Feb 06; 506(7486):52-7.
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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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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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Stochastic cytokine expression induces mixed T helper cell States. PLoS Biol. 2013 Jul; 11(7):e1001618.
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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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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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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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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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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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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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IAP inhibitors enhance co-stimulation to promote tumor immunity. J Exp Med. 2010 Sep 27; 207(10):2195-206.
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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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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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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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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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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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Microsomal triglyceride transfer protein in plasma and cellular lipid metabolism. Curr Opin Lipidol. 2008 Jun; 19(3):277-84.
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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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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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CD1 expression on antigen-presenting cells. Curr Top Microbiol Immunol. 2007; 314:113-41.
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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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A rare cause of abdominal pain. Gut. 2004 Sep; 53(9):1261, 1266.
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Drosophila wingless generates cell type diversity among engrailed expressing cells. Nature. 1992 Nov 26; 360(6402):347-50.
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