Photo of Mark A. Exley,  PhD

Mark A. Exley, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital


mexley@partners.org

Mark A. Exley, PhD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

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Our primary research interests are in regulation of the immune system by CD1d-reactive NKT cells and how to utilize this knowledge clinically in cancer and other diseases. CD1d is expressed on myeloid cells, lymphocytes, heart, liver, and in the gut. Bi-directional interactions between CD1d+ cells and CD1d-reactive NKT profoundly influence immune responses. Our recent contributions include establishing a physiological role for CD1d-reactive NKT and defining the human populations of these cells in health and disease. Advanced cancer patients have few and anti-inflammatory polarized CD1d-reactive NKT, which may suppress their anti-tumor activity. Bone marrow CD1d-reactive T cells have a profound anti-inflammatory bias with potential to suppress graft-versus-host disease. Conversely, HCV+ human liver also contains large numbers of CD1d-reactive NKT, but with a pro-inflammatory bias, which may contribute to both protective and pathogenic responses in hepatitis and hepatocellular carcinoma. These results support a role for these cells in immune decision making with potential therapeutic applications. We are supporting clinical trials to exploit NKT cells in cancer and other diseases. We are also following up identification of a physiological role for CD1d-reactive NKT in resistance to viral infections through activation of NK and conventional T cells. Finally, we have identified a protective role of NKT cells in obesity and consequent metabolic syndrome.

Publications

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  • Wen X, Kim S, Xiong R, Li M, Lawrenczyk A, Huang X, Chen SY, Rao P, Besra GS, Dellabona P, Casorati G, Porcelli SA, Akbari O, Exley MA, Yuan W. A Subset of CD8αβ+ Invariant NKT Cells in a Humanized Mouse Model. J Immunol 2015. PubMed
  • Exley MA, Hand L, O'Shea D, Lynch L. Interplay between the immune system and adipose tissue in obesity. J Endocrinol 2014; 223:R41-8. PubMed
  • Zeng SG, Ghnewa YG, O'Reilly VP, Lyons VG, Atzberger A, Hogan AE, Exley MA, Doherty DG. Human invariant NKT cell subsets differentially promote differentiation, antibody production, and T cell stimulation by B cells in vitro. J Immunol 2013; 191:1666-76. PubMed
  • Mangan BA, Dunne MR, O'Reilly VP, Dunne PJ, Exley MA, O'Shea D, Scotet E, Hogan AE, Doherty DG. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vδ3 T cells. J Immunol 2013; 191:30-4. PubMed
  • Li S, Vriend LE, Nasser IA, Popov Y, Afdhal NH, Koziel MJ, Schuppan D, Exley MA, Alatrakchi N. Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology 2012. PubMed
  • Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O'Shea D, O'Farrelly C, Exley MA. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 2012; 37:574-87. PubMed
  • Exley MA. Editorial: NKT get the 'flu: NKT cells as (mostly) good guys in influenza; monocytic cells as double agents. J Leukoc Biol 2012; 91:349-52. PubMed
  • Exley MA, Lynch L, Varghese B, Nowak M, Alatrakchi N, Balk SP. Developing understanding of the roles of CD1d-restricted T cell subsets in cancer: reversing tumor-induced defects. Clin Immunol 2011; 140:184-95. PubMed
  • Exley MA, Nakayama T. NKT-cell-based immunotherapies in clinical trials. Clin Immunol 2011; 140:117-8. PubMed
  • 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; 120:2889-99. PubMed
  • Exley MA, Wilson B, Balk SP. Isolation and functional use of human NKT cells. Curr Protoc Immunol 2010; Chapter 14:Unit 14.11. PubMed
  • Nowak M, Lynch L, Yue S, Ohta A, Sitkovsky M, Balk SP, Exley MA. The A2aR adenosine receptor controls cytokine production in iNKT cells. Eur J Immunol 2010; 40:682-7. PubMed
  • Yue SC, Nowak M, Shaulov-Kask A, Wang R, Yue D, Balk SP, Exley MA. Direct CD1d-mediated stimulation of APC IL-12 production and protective immune response to virus infection in vivo. J Immunol 2009; 184:268-76. PubMed
  • Nowak M, Arredouani MS, Tun-Kyi A, Schmidt-Wolf I, Sanda MG, Balk SP, Exley MA. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with alpha-galactosylceramide. PLoS ONE 2010; 5:e11311. PubMed
  • Teng MW, Sharkey J, McLaughlin NM, Exley MA, Smyth MJ. CD1d-based combination therapy eradicates established tumors in mice. J Immunol 2009; 183:1911-20. PubMed
  • Teng MW,Yue S,Sharkey J,Exley MA,Smyth MJ. CD1d activation and blockade: a new antitumor strategy. J Immunol 2009; 182:3366-71. PubMed
  • Song W,van der Vliet HJ,Tai YT,Prabhala R,Wang R,Podar K,Catley L,Shammas MA,Anderson KC,Balk SP,Exley MA,Munshi NC. Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin Cancer Res 2008; 14:6955-62. PubMed
  • Exley MA,Hou R,Shaulov A,Tonti E,Dellabona P,Casorati G,Akbari O,Akman HO,Greenfield EA,Gumperz JE,Boyson JE,Balk SP,Wilson SB. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. Eur J Immunol 2008; 38:1756-66. PubMed
  • van der Vliet HJ,Wang R,Yue SC,Koon HB,Balk SP,Exley MA. Circulating myeloid dendritic cells of advanced cancer patients result in reduced activation and a biased cytokine profile in invariant NKT cells. J Immunol 2008; 180:7287-93. PubMed
  • Shaulov A, Yue S, Wang R, Joyce RM, Balk SP, Kim HT, Avigan DE, Uhl L, Sackstein R, Exley MA. Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: Implications for posttransplant survival. Exp Hematol 2008; 36:464-72. PubMed
  • van der Vliet HJ, Koon HB, Atkins MB, Balk SP, Exley MA. Exploiting regulatory T-cell populations for the immunotherapy of cancer. J Immunother 2007; 30:591-5. PubMed
  • Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ. Hepatitis C Virus (HCV)-Specific CD8+ Cells Produce Transforming Growth Factor {beta} That Can Suppress HCV-Specific T-Cell Responses. J Virol 2007; 81:5882-92. PubMed
  • Speak AO, Salio M, Neville DC, Fontaine J, Priestman DA, Platt N, Heare T, Butters TD, Dwek RA, Trottein F, Exley MA, Cerundolo V, Platt FM. Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals. Proc Natl Acad Sci U S A 2007; 104:5971-6. PubMed
  • van Dervliet HJ, Koon HB, Yue SC, Uzunparmak B, Seery V, Gavin MA, Rudensky AY, Atkins MB, Balk SP, Exley MA. Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer. Clin Cancer Res 2007; 13:2100-8. PubMed
  • Yanagisawa K, Exley MA, Jiang X, Ohkochi N, Taniguchi M, Seino K. Hyporesponsiveness to natural killer T-cell ligand alpha-galactosylceramide in cancer-bearing state mediated by CD11b+ Gr-1+ cells producing nitric oxide. Cancer Res 2006; 66:11441-6. PubMed
  • van der Vliet HJ, Balk SP, Exley MA. Natural killer T cell-based cancer immunotherapy. Clin Cancer Res 2006; 12:5921-3. PubMed
  • Lang GA, Exley MA, Lang ML. The CD1d-binding glycolipid alpha-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology 2006; 119:116-25. PubMed
  • Ilyinskii PO, Wang R, Balk SP, Exley MA. CD1d mediates T-cell-dependent resistance to secondary infection with encephalomyocarditis virus (EMCV) in vitro and immune response to EMCV infection in vivo. J Virol 2006; 80:7146-58. PubMed
  • Boyson JE, Nagarkatti N, Nizam L, Exley MA, Strominger JL. Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss. Proc Natl Acad Sci U S A 2006; 103:4580-5. PubMed
  • 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; 202:529-39. PubMed
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