Photo of Vassiliki A. Boussiotis,  MD, PhD

Vassiliki A. Boussiotis, MD, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-8563
Fax: (617) 667-3299


vboussio@bidmc.harvard.edu

Vassiliki A. Boussiotis, MD, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Professor, BIDMC Cancer Center, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

My research group is investigating mechanisms and signaling pathways involved in regulation of activating and inhibitory T cell responses. Mechanistic understanding of signaling and molecular pathways that regulate T cell responses is of major therapeutic interest in cancer. Specifically, targeted intervention to such pathways provides the means to modulate the immune responses either for augmentation in order to induce anti-tumor immunity or for suppression in order to prevent graft versus host disease, which is the leading cause of non-relapse mortality in patients with hematologic malignancies, who receive allogeneic hematopoietic stem cell transplantation.

Lymphocyte activation requires adhesion to antigen presenting cells. This is a critical event linking innate and adaptive immunity and a mandatory step for the initiation of T cell immune responses. Lymphocyte adhesion is accomplished through the regulation of the principle adhesion molecule on the lymphocyte surface, LFA-1. In order to mediate its adhesive function LFA-1 must be activated via a process referred to as inside-out signaling. Among the few signaling molecules that have been implicated in this process in hematopoietic cells are the small GTPase Rap1 and its downstream effector RIAM, a multidomain protein. RIAM was discovered in our laboratory and defined the MRL class of adaptors. We are studying the dynamic integration of RIAM in signaling assemblies and signal transduction pathways and the mechanistic role of RIAM in the regulation of T cell responses.

Our laboratory was among the first to demonstrate that the induction of T cell anergy in vitro and tolerance in vivo result from active signaling processes. These early observations were verified with the recent developments in the field of immune tolerance and the discovery of the PD-1: PDL1/2 pathway, which has a central and mandatory role in the induction and maintenance of peripheral tolerance. Currently, we are dissecting the mechanisms of PD-1-mediated inhibition of T cell activation at the cellular and signaling level.

Our group is part of hematopoietic stem cell transplantation research team at the Dana-Farber / Harvard Cancer Center (DFCI/HCC). Our ultimate goal is to translate our findings from basic T cell biology into novel approaches for induction of anti-tumor immunity, prevention of GvHD and improvement of immune reconstitution after allogeneic hematopoietic stem cell transplantation.

 

Publications

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  • Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6:6692. PubMed
  • Politikos I, Kim HT, Nikiforow S, Li L, Brown J, Antin JH, Cutler C, Ballen K, Ritz J, Boussiotis VA. IL-7 and SCF Levels Inversely Correlate with T Cell Reconstitution and Clinical Outcomes after Cord Blood Transplantation in Adults. PLoS ONE 2015; 10:e0132564. PubMed
  • Boussiotis VA. Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma. N Engl J Med 2014; 371:2230-2. PubMed
  • Politikos I, Boussiotis VA. The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. Blood 2014. PubMed
  • Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol 2013; 33:3091-8. PubMed
  • Medraño-Fernandez I, Reyes R, Olazabal I, Rodriguez E, Sanchez-Madrid F, Boussiotis VA, Reche PA, Cabañas C, Lafuente EM. RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis. Cell Mol Life Sci 2013. PubMed
  • Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T, Dey BR, Somaiya P, Mills H, Campigotto F, Weller E, Joyce R, Levine JD, Tzachanis D, Richardson P, Laubach J, Raje N, Boussiotis V, Yuan YE, Bisharat L, Held V, Rowe J, Anderson K, Kufe D, Avigan D. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013; 19:3640-8. PubMed
  • Ballen K, Mendizabal AM, Cutler C, Politikos I, Jamieson K, Shpall EJ, Dey BR, Attar E, McAfee S, Delaney C, McCarthy P, Ball ED, Kamble R, Avigan D, Maziarz RT, Ho VT, Koreth J, Alyea E, Soiffer R, Wingard JR, Boussiotis V, Spitzer TR, Antin JH. Phase II trial of parathyroid hormone after double umbilical cord blood transplantation. Biol Blood Marrow Transplant 2012; 18:1851-8. PubMed
  • Patsoukis N, Sari D, Boussiotis VA. PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell Cycle 2012; 11:4305-9. PubMed
  • Wynne JP, Wu J, Su W, Mor A, Patsoukis N, Boussiotis VA, Hubbard SR, Philips MR. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J Cell Biol 2012; 199:317-30. PubMed
  • Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 2012; 5:ra46. PubMed
  • Li L, Patsoukis N, Petkova V, Boussiotis VA. Runx1 and Runx3 are involved in the generation and function of highly suppressive IL-17-producing T regulatory cells. PLoS ONE 2012; 7:e45115. PubMed
  • Hernández-Varas P, Coló GP, Bartolomé RA, Paterson A, Medraño-Fernández I, Arellano-Sánchez N, Cabañas C, Sánchez-Mateos P, Lafuente EM, Boussiotis VA, Strömblad S, Teixidó J. Rap1-GTP-interacting adaptor molecule (RIAM) protein controls invasion and growth of melanoma cells. J Biol Chem 2011. PubMed
  • Li L, Kim J, Boussiotis VA. IL-1硫-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol 2010; 185:4148-53. PubMed
  • Rosenblatt J, Bissonnette A, Ahmad R, Wu Z, Vasir B, Stevenson K, Zarwan C, Keefe W, Glotzbecker B, Mills H, Joyce R, Levine JD, Tzachanis D, Boussiotis V, Kufe D, Avigan D. Immunomodulatory effects of vitamin D: implications for GVHD. Bone Marrow Transplant 2010; 45:1463-8. PubMed
  • Cutler C, Stevenson K, Kim HT, Brown J, McDonough S, Herrera M, Reynolds C, Liney D, Kao G, Ho V, Armand P, Koreth J, Alyea E, Dey BR, Attar E, Spitzer T, Boussiotis VA, Ritz J, Soiffer R, Antin JH, Ballen K. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis. Bone Marrow Transplant 2010. PubMed
  • Brown JA, Stevenson K, Kim HT, Cutler C, Ballen K, McDonough S, Reynolds C, Herrera M, Liney D, Ho V, Kao G, Armand P, Koreth J, Alyea E, McAfee S, Attar E, Dey B, Spitzer T, Soiffer R, Ritz J, Antin JH, Boussiotis VA. Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis. Blood 2010; 115:4111-9. PubMed
  • Li L, Kim JS, Boussiotis VA. Rap1A regulates generation of T regulatory cells via LFA-1-dependent and LFA-1-independent mechanisms. Cell Immunol 2010; 266:7-13. PubMed
  • Tzachanis D,Boussiotis VA. Tob, a member of the APRO family, regulates immunological quiescence and tumor suppression. Cell Cycle 2009; 8:1019-25. PubMed
  • Patsoukis N, Lafuente EM, Meraner P, Kim J, Dombkowski D, Li L, Boussiotis VA. RIAM regulates the cytoskeletal distribution and activation of PLC-gamma1 in T cells. Sci Signal 2009; 2:ra79. PubMed
  • Zhou D,Medoff BD,Chen L,Li L,Zhang XF,Praskova M,Liu M,Landry A,Blumberg RS,Boussiotis VA,Xavier R,Avruch J. The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells. Proc Natl Acad Sci U S A 2008; 105:20321-6. PubMed
  • Watanabe N,Bodin L,Pandey M,Krause M,Coughlin S,Boussiotis VA,Ginsberg MH,Shattil SJ. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin alphaIIbbeta3. J Cell Biol 2008; 181:1211-22. PubMed
  • Brown JA,Boussiotis VA. Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clin Immunol 2008; 127:286-97. PubMed
  • Ge X, Brown J, Sykes M, Boussiotis VA. CD134-allodepletion allows selective elimination of alloreactive human T cells without loss of virus-specific and leukemia-specific effectors. Biol Blood Marrow Transplant 2008; 14:518-30. PubMed
  • Rosenblatt J, Wu Z, Vasir B, Zarwan C, Stone R, Mills H, Friedman T, Konstantinopoulos PA, Spentzos D, Ghebremichael M, Stevenson K, Neuberg D, Levine JD, Joyce R, Tzachanis D, Boussiotis V, Kufe D, Avigan D. Generation of Tumor-specific T Lymphocytes Using Dendritic Cell/Tumor Fusions and Anti-CD3/CD28. J Immunother 2010; 33:155-66. PubMed
  • Nellore A, Liu B, Patsoukis N, Boussiotis VA, Li L. The cyclin dependent kinase inhibitor (R)-roscovitine mediates selective suppression of alloreactive human T cells but preserves pathogen-specific and leukemia-specific effectors. Clin Immunol 2014; 152:48-57. PubMed
  • Boussiotis VA, Chatterjee P, Li L. Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J 2014; 20:265-71. PubMed
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