Photo of Michael Dougan,  MD, PhD

Michael Dougan, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6122


mldougan@partners.org

Michael Dougan, MD, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Assistant in Medicine, Medicine, Division of Gastroenterology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

I have a longstanding interest in interaction between the immune system and cancer. As a dissertation student with Dr. Glenn Dranoff’s lab at Dana-Farber Cancer Institute, I established the first model of lung cancer caused by a defect in immune regulation. In this model, deficiencies in the cytokines GM-CSF, IL-3 and IFN-γ, lead to a combination of tumor promoting inflammation and defective antitumor immunity that produces highly penetrant pulmonary adenocarcinomas. This work provided early pre-clinical data supporting a dual role for the immune response in lung cancer, with failure of adaptive immunity combining with innate inflammation to drive lung cancer development. These findings were subsequently validated in clinical trials of checkpoint blockade which confirmed a role for adaptive immunity in controlling lung cancer, and in the CANTOS trial which demonstrated reduced lung cancer incidents in patients treated with antibodies that block the innate inflammatory cytokine IL-1β.

My dissertation work also identified a novel regulatory role for the Inhibitor of Apoptosis (IAP) family of proteins in T cell activation through NF-B signaling downstream of TNF family costimulatory receptors. I used pharmacologic IAP inhibitors to study the therapeutic implications of this finding, combining IAP antagonists with a tumor vaccine to augment antitumor responses. This finding was the basis for subsequent work that has exploited the immune modulating properties of IAP antagonists to treat multiple myeloma and glioblastoma in preclinical models, and is now being investigated in multiple clinical trials.

As a resident and Gastroenterology fellow at Massachusetts General Hospital (MGH), I joined Dr. Hidde Ploegh’s lab at the Whitehead Institute for Biomedical Research, where I generated and characterized single domain antibodies (VHHs) to several immune receptors. I used these VHHs for multiple pre-clinical applications. By fusing VHHs to cytokines, I developed a panel of modified cytokines with novel binding properties and improved therapeutic effects in a variety of mouse models. I showed that VHHs against CD47 can enhance responses to murine melanoma in combination with immune modulating antibodies, and in my own lab, have established a syngeneic model for evaluating the toxicities of CD47 targeted therapeutics. By tagging these VHH to radioisotopes, I worked with two other postdoctoral fellows to comprehensively image PD-L1 in a live mouse, and to track CD8 T cells responses in mice undergoing immunotherapy using immuno-positron emission tomography (PET). PD-L1 PET unexpectedly showed that PD-L1 is primarily expression by brown adipose tissue (BAT), and is an activation-independent marker for brown adipocytes, a finding with implications that I continue to explore in my own lab.

As an independent investigator, I have focused my efforts on understanding the etiology and immune mechanisms underlying the immune-related adverse events (irAEs) resulting from cancer immunotherapy, a window into the endogenous function of the immune receptors targeted by these therapies. My research dovetails with my clinical work, where I specialize in treating gastrointestinal (GI) irAEs resulting from “checkpoint” receptor blockade, which are often treatment limiting. Management relies on systemic corticosteroids, which are likely to have deleterious effects on antitumor responses. My goal is to use a detailed mechanistic understanding of gastrointestinal irAEs to develop novel treatment strategies that do not interfere with antitumor immunity, as well as to understand on a more fundamental level, how individual immune receptors regulate immune homeostasis in the GI tract.

Publications

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  • Dougan M, Dougan SK. Programmable bacteria as cancer therapy. Nat Med 2019. PubMed
  • Pauken KE, Dougan M, Rose NR, Lichtman AH, Sharpe AH. Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities. Trends Immunol 2019; 40:511-523. PubMed
  • Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation. Immunity 2019; 50:796-811. PubMed
  • Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, Momin N, Pishesha N, Rickelt S, Hynes RO, Ploegh H. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci U S A 2019. PubMed
  • Bello E, Cohen JV, Mino-Kenudson M, Dougan M. Antitumor response to microscopic melanoma in the gastric mucosa mimicking ipilimumab-induced gastritis. J Immunother Cancer 2019; 7:41. PubMed
  • Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, Ali LR, Quijano-Rubio A, Ruterbusch M, Leung I, Biary T, Crowley SJ, Marcos E, Walkey CD, Weitzner BD, Pardo-Avila F, Castellanos J, Carter L, Stewart L, Riddell SR, Pepper M, Bernardes GJL, Dougan M, Garcia KC, Baker D. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 2019; 565:186-191. PubMed
  • Reynolds K, Thomas M, Dougan M. Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade. Oncologist 2018; 23:991-997. PubMed
  • Dougan SK, Dougan M. Regulation of innate and adaptive antitumor immunity by IAP antagonists. 2018. PubMed
  • 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. PubMed
  • 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; 6:389-401. PubMed
  • 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. PubMed
  • 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; 6:25-35. PubMed
  • 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; 8:647. PubMed
  • 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; 114:10184-10189. PubMed
  • Rashidian M, Ingram JR, Dougan M, Dongre A, Whang KA, LeGall C, Cragnolini JJ, Bierie B, Gostissa M, Gorman J, Grotenbreg GM, Bhan A, Weinberg RA, Ploegh HL. Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med 2018; 214:2243-2255. PubMed
  • Dougan M, Dougan SK. Targeting Immunotherapy to the Tumor Microenvironment. J Cell Biochem 2017. PubMed
  • 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. PubMed
  • Dougan M. Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract. 2017; 8:1547. PubMed
  • Sockolosky JT, Dougan M, Ingram JR, Ho CC, Kauke MJ, Almo SC, Ploegh HL, Garcia KC. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A 2018; 113:E2646-54. PubMed
  • 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. 2017; 11:e1005188. PubMed
  • Rashidian M, Keliher E, Dougan M, Juras PK, Cavallari M, Wojtkiewicz GR, Jacobsen J, Edens JG, Tas JM, Victora G, Weissleder R, Ploegh H. The use of F-2-fluorodeoxyglucose (FDG) to label antibody fragments for immuno-PET of pancreatic cancer. ACS Cent Sci 2017; 1:142-147. PubMed
  • 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 2014; 1:99-111. PubMed
  • Dougan M, Li D, Neuberg D, Mihm M, Googe P, Wong KK, Dranoff G. A dual role for the immune response in a mouse model of inflammation-associated lung cancer. J Clin Invest 2011; 121:2436-46. PubMed
  • 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; 207:2195-206. PubMed
  • Dougan M,Dranoff G. The immune response to tumors. Curr Protoc Immunol 2009; Chapter 20:Unit 20.11. PubMed
  • Dougan M,Dranoff G. Immune therapy for cancer. Annu Rev Immunol 2008; 27:83-117. PubMed
  • Dougan M, Dranoff G. Inciting inflammation: the RAGE about tumor promotion. J Exp Med 2008; 205:267-70. PubMed
  • Enzler T, Gillessen S, Dougan M, Allison JP, Neuberg D, Oble DA, Mihm M, Dranoff G. Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of beta cells. Blood 2007; 110:954-61. PubMed
  • Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G. MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 2007; 117:1902-13. PubMed
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