Boussiotis, Vassiliki

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Boussiotis, Vassiliki

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Boussiotis

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Vassiliki

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Boussiotis, Vassiliki

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Immunotherapies for Malignant Glioma
(2017) Boussiotis, Vassiliki; Charest, Alain
Glioblastoma Multiforme (GBM) is a highly malignant primary brain cancer with a dreadful overall survival and for which treatment options are limited. Recent breakthroughs in novel immune-related treatment strategies for cancer have spurred interests in usurping the power of the patient's immune system to recognize and eliminate GBM. Here, we discuss the unique properties of GBM's tumor microenvironment, the effects of GBM standard on care therapy on tumor-associated immune cells and review several approaches aimed at therapeutically targeting the immune system for GBM treatment. We believe that a comprehensive understanding of the intricate micro-environmental landscape of GBM will abound into the development of novel immunotherapy strategies for GBM patients.
Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2
(Impact Journals LLC, 2016) Christofides, Anthos; Karantanos, Theodoros; Bardhan, Kankana; Boussiotis, Vassiliki
Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.
Clinical significance of T cell metabolic reprogramming in cancer
(Springer Berlin Heidelberg, 2016) Herbel, Christoph; Patsoukis, Nikolaos; Bardhan, Kankana; Seth, Pankaj; Weaver, Jessica D.; Boussiotis, Vassiliki
Conversion of normal cells to cancer is accompanied with changes in their metabolism. During this conversion, cell metabolism undergoes a shift from oxidative phosphorylation to aerobic glycolysis, also known as Warburg effect, which is a hallmark for cancer cell metabolism. In cancer cells, glycolysis functions in parallel with the TCA cycle and other metabolic pathways to enhance biosynthetic processes and thus support proliferation and growth. Similar metabolic features are observed in T cells during activation but, in contrast to cancer, metabolic transitions in T cells are part of a physiological process. Currently, there is intense interest in understanding the cause and effect relationship between metabolic reprogramming and T cell differentiation. After the recent success of cancer immunotherapy, the crosstalk between immune system and cancer has come to the forefront of clinical and basic research. One of the key goals is to delineate how metabolic alterations of cancer influence metabolism-regulated function and differentiation of tumor resident T cells and how such effects might be altered by immunotherapy. Here, we review the unique metabolic features of cancer, the implications of cancer metabolism on T cell metabolic reprogramming during antigen encounters, and the translational prospective of harnessing metabolism in cancer and T cells for cancer therapy.
The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation
(Frontiers Media S.A., 2016) Bardhan, Kankana; Anagnostou, Theodora; Boussiotis, Vassiliki
The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one: National Harbor, MD, USA. 9-13 November 2016
(BioMed Central, 2016) Lundqvist, Andreas; van Hoef, Vincent; Zhang, Xiaonan; Wennerberg, Erik; Lorent, Julie; Witt, Kristina; Sanz, Laia Masvidal; Liang, Shuo; Murray, Shannon; Larsson, Ola; Kiessling, Rolf; Mao, Yumeng; Sidhom, John-William; Bessell, Catherine A.; Havel, Jonathan; Schneck, Jonathan; Chan, Timothy A.; Sachsenmeier, Eliot; Woods, David; Berglund, Anders; Ramakrishnan, Rupal; Sodre, Andressa; Weber, Jeffrey; Zappasodi, Roberta; Li, Yanyun; Qi, Jingjing; Wong, Philip; Sirard, Cynthia; Postow, Michael; Newman, Walter; Koon, Henry; Velcheti, Vamsidhar; Callahan, Margaret K.; Wolchok, Jedd D.; Merghoub, Taha; Lum, Lawrence G.; Choi, Minsig; Thakur, Archana; Deol, Abhinav; Dyson, Gregory; Shields, Anthony; Haymaker, Cara; Uemura, Marc; Murthy, Ravi; James, Marihella; Wang, Daqing; Brevard, Julie; Monaghan, Catherine; Swann, Suzanne; Geib, James; Cornfeld, Mark; Chunduru, Srinivas; Agrawal, Sudhir; Yee, Cassian; Wargo, Jennifer; Patel, Sapna P.; Amaria, Rodabe; Tawbi, Hussein; Glitza, Isabella; Woodman, Scott; Hwu, Wen-Jen; Davies, Michael A.; Hwu, Patrick; Overwijk, Willem W.; Bernatchez, Chantale; Diab, Adi; Massarelli, Erminia; Segal, Neil H.; Ribrag, Vincent; Melero, Ignacio; Gangadhar, Tara C.; Urba, Walter; Schadendorf, Dirk; Ferris, Robert L.; Houot, Roch; Morschhauser, Franck; Logan, Theodore; Luke, Jason J.; Sharfman, William; Barlesi, Fabrice; Ott, Patrick A.; Mansi, Laura; Kummar, Shivaani; Salles, Gilles; Carpio, Cecilia; Meier, Roland; Krishnan, Suba; McDonald, Dan; Maurer, Matthew; Gu, Xuemin; Neely, Jaclyn; Suryawanshi, Satyendra; Levy, Ronald; Khushalani, Nikhil; Wu, Jennifer; Zhang, Jinyu; Basher, Fahmin; Rubinstein, Mark; Bucsek, Mark; Qiao, Guanxi; MacDonald, Cameron; Hylander, Bonnie; Repasky, Elizabeth; Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita; Toth, Kyle; Meek, Megan; Garrett-Mayer, Elizabeth; Nishimura, Michael; Paulos, Chrystal; Beeson, Craig; Yu, Xuezhong; Mehrotra, Shikhar; Zhao, Fei; Evans, Kathy; Xiao, Christine; Holtzhausen, Alisha; Hanks, Brent A.; Scharping, Nicole; Menk, Ashley V.; Moreci, Rebecca; Whetstone, Ryan; Dadey, Rebekah; Watkins, Simon; Ferris, Robert; Delgoffe, Greg M.; Peled, Jonathan; Devlin, Sean; Staffas, Anna; Lumish, Melissa; Rodriguez, Kori Porosnicu; Ahr, Katya; Perales, Miguel; Giralt, Sergio; Taur, Ying; Pamer, Eric; van den Brink, Marcel R. M.; Jenq, Robert; Annels, Nicola; Pandha, Hardev; Simpson, Guy; Mostafid, Hugh; Harrington, Kevin; Melcher, Alan; Grose, Mark; Davies, Bronwyn; Au, Gough; Karpathy, Roberta; Shafren, Darren; Ricca, Jacob; Zamarin, Dmitriy; Batista, Luciana; Marliot, Florence; Vasaturo, Angela; Carpentier, Sabrina; Poggionovo, Cécile; Frayssinet, Véronique; Fieschi, Jacques; Van den Eynde, Marc; Pagès, Franck; Galon, Jérôme; Hermitte, Fabienne; Smith, Sean G.; Nguyen, Khue; Ravindranathan, Sruthi; Koppolu, Bhanu; Zaharoff, David; Schvartsman, Gustavo; Bassett, Roland; McQuade, Jennifer L.; Haydu, Lauren E.; Kline, Douglas; Chen, Xiufen; Fosco, Dominick; Kline, Justin; Overacre, Abigail; Chikina, Maria; Brunazzi, Erin; Shayan, Gulidanna; Horne, William; Kolls, Jay; Bruno, Tullia C.; Workman, Creg; Vignali, Dario; Adusumilli, Prasad S.; Ansa-Addo, Ephraim A; Li, Zihai; Gerry, Andrew; Sanderson, Joseph P.; Howe, Karen; Docta, Roslin; Gao, Qian; Bagg, Eleanor A. L.; Tribble, Nicholas; Maroto, Miguel; Betts, Gareth; Bath, Natalie; Melchiori, Luca; Lowther, Daniel E.; Ramachandran, Indu; Kari, Gabor; Basu, Samik; Binder-Scholl, Gwendolyn; Chagin, Karen; Pandite, Lini; Holdich, Tom; Amado, Rafael; Zhang, Hua; Glod, John; Bernstein, Donna; Jakobsen, Bent; Mackall, Crystal; Wong, Ryan; Silk, Jonathan D.; Adams, Katherine; Hamilton, Garth; Bennett, Alan D.; Brett, Sara; Jing, Junping; Quattrini, Adriano; Saini, Manoj; Wiedermann, Guy; Brewer, Joanna; Duong, MyLinh; Lu, An; Chang, Peter; Mahendravada, Aruna; Shinners, Nicholas; Slawin, Kevin; Spencer, David M.; Foster, Aaron E.; Bayle, J. Henri; Bergamaschi, Cristina; Ng, Sinnie Sin Man; Nagy, Bethany; Jensen, Shawn; Hu, Xintao; Alicea, Candido; Fox, Bernard; Felber, Barbara; Pavlakis, George; Chacon, Jessica; Yamamoto, Tori; Garrabrant, Thomas; Cortina, Luis; Powell, Daniel J.; Donia, Marco; Kjeldsen, Julie Westerlin; Andersen, Rikke; Westergaard, Marie Christine Wulff; Bianchi, Valentina; Legut, Mateusz; Attaf, Meriem; Dolton, Garry; Szomolay, Barbara; Ott, Sascha; Lyngaa, Rikke; Hadrup, Sine Reker; Sewell, Andrew Kelvin; Svane, Inge Marie; Fan, Aaron; Kumai, Takumi; Celis, Esteban; Frank, Ian; Stramer, Amanda; Blaskovich, Michelle A.; Wardell, Seth; Fardis, Maria; Bender, James; Lotze, Michael T.; Goff, Stephanie L.; Zacharakis, Nikolaos; Assadipour, Yasmine; Prickett, Todd D.; Gartner, Jared J.; Somerville, Robert; Black, Mary; Xu, Hui; Chinnasamy, Harshini; Kriley, Isaac; Lu, Lily; Wunderlich, John; Robbins, Paul F.; Rosenberg, Steven; Feldman, Steven A.; Trebska-McGowan, Kasia; Malekzadeh, Parisa; Payabyab, Eden; Sherry, Richard; Gokuldass, Aishwarya; Kopits, Charlene; Rabinovich, Brian; Green, Daniel S.; Kamenyeva, Olena; Zoon, Kathryn C.; Annunziata, Christina M.; Hammill, Joanne; Helsen, Christopher; Aarts, Craig; Bramson, Jonathan; Harada, Yui; Yonemitsu, Yoshikazu; Mwawasi, Kenneth; Denisova, Galina; Giri, Rajanish; Jin, Benjamin; Campbell, Tracy; Draper, Lindsey M.; Stevanovic, Sanja; Yu, Zhiya; Weissbrich, Bianca; Restifo, Nicholas P.; Trimble, Cornelia L.; Hinrichs, Christian S.; Tsang, Kwong; Fantini, Massimo; Hodge, James W.; Fujii, Rika; Fernando, Ingrid; Jochems, Caroline; Heery, Christopher; Gulley, James; Soon-Shiong, Patrick; Schlom, Jeffrey; Jing, Weiqing; Gershan, Jill; Blitzer, Grace; Weber, James; McOlash, Laura; Johnson, Bryon D.; Kiany, Simin; Gangxiong, Huang; Kleinerman, Eugenie S.; Klichinsky, Michael; Ruella, Marco; Shestova, Olga; Kenderian, Saad; Kim, Miriam; Scholler, John; June, Carl H.; Gill, Saar; Moogk, Duane; Zhong, Shi; Liadi, Ivan; Rittase, William; Fang, Victoria; Dougherty, Janna; Perez-Garcia, Arianne; Osman, Iman; Zhu, Cheng; Varadarajan, Navin; Frey, Alan; Krogsgaard, Michelle; Landi, Daniel; Fousek, Kristen; Mukherjee, Malini; Shree, Ankita; Joseph, Sujith; Bielamowicz, Kevin; Byrd, Tiara; Ahmed, Nabil; Hegde, Meenakshi; Lee, Sylvia; Byrd, David; Thompson, John; Bhatia, Shailender; Tykodi, Scott; Delismon, Judy; Chu, Liz; Abdul-Alim, Siddiq; Ohanian, Arpy; DeVito, Anna Marie; Riddell, Stanley; Margolin, Kim; Magalhaes, Isabelle; Mattsson, Jonas; Uhlin, Michael; Nemoto, Satoshi; Villarroel, Patricio Pérez; Nakagawa, Ryosuke; Mule, James J.; Mailloux, Adam W.; Mata, Melinda; Nguyen, Phuong; Gerken, Claudia; DeRenzo, Christopher; Gottschalk, Stephen; Mathieu, Mélissa; Pelletier, Sandy; Stagg, John; Turcotte, Simon; Minutolo, Nicholas; Sharma, Prannda; Tsourkas, Andrew; Mockel-Tenbrinck, Nadine; Mauer, Daniela; Drechsel, Katharina; Barth, Carola; Freese, Katharina; Kolrep, Ulrike; Schult, Silke; Assenmacher, Mario; Kaiser, Andrew; Mullinax, John; Hall, MacLean; Le, Julie; Kodumudi, Krithika; Royster, Erica; Richards, Allison; Gonzalez, Ricardo; Sarnaik, Amod; Pilon-Thomas, Shari; Nielsen, Morten; Krarup-Hansen, Anders; Hovgaard, Dorrit; Petersen, Michael Mørk; Loya, Anand Chainsukh; Junker, Niels; Rivas, Charlotte; Parihar, Robin; Rooney, Cliona M.; Qin, Haiying; Nguyen, Sang; Su, Paul; Burk, Chad; Duncan, Brynn; Kim, Bong-Hyun; Kohler, M. Eric; Fry, Terry; Rao, Arjun A.; Teyssier, Noam; Pfeil, Jacob; Sgourakis, Nikolaos; Salama, Sofie; Haussler, David; Richman, Sarah A.; Nunez-Cruz, Selene; Gershenson, Zack; Mourelatos, Zissimos; Barrett, David; Grupp, Stephan; Milone, Michael; Rodriguez-Garcia, Alba; Robinson, Matthew K.; Adams, Gregory P.; Santos, João; Havunen, Riikka; Siurala, Mikko; Cervera-Carrascón, Víctor; Parviainen, Suvi; Antilla, Marjukka; Hemminki, Akseli; Sethuraman, Jyothi; Santiago, Laurelis; Chen, Jie Qing; Dai, Zhimin; Sha, Huizi; Su, Shu; Ding, Naiqing; Liu, Baorui; Pasetto, Anna; Helman, Sarah R.; Rosenberg, Steven A.; Burgess, Melissa; Zhang, Hui; Lee, Tien; Klingemann, Hans; Nghiem, Paul; Kirkwood, John M.; Rossi, John M.; Sherman, Marika; Xue, Allen; Shen, Yueh-wei; Navale, Lynn; Kochenderfer, James N.; Bot, Adrian; Veerapathran, Anandaraman; Wiener, Doris; Waller, Edmund K.; Li, Jian-Ming; Petersen, Christopher; Blazar, Bruce R.; Li, Jingxia; Giver, Cynthia R.; Wang, Ziming; Grossenbacher, Steven K.; Sturgill, Ian; Canter, Robert J.; Murphy, William J.; Zhang, Congcong; Burger, Michael C.; Jennewein, Lukas; Waldmann, Anja; Mittelbronn, Michel; Tonn, Torsten; Steinbach, Joachim P.; Wels, Winfried S.; Williams, Jason B.; Zha, Yuanyuan; Gajewski, Thomas F.; Williams, LaTerrica C.; Krenciute, Giedre; Kalra, Mamta; Louis, Chrystal; Xin, Gang; Schauder, David; Jiang, Aimin; Joshi, Nikhil; Cui, Weiguo; Zeng, Xue; Zhao, Zeguo; Hamieh, Mohamad; Eyquem, Justin; Gunset, Gertrude; Bander, Neil; Sadelain, Michel; Askmyr, David; Abolhalaj, Milad; Lundberg, Kristina; Greiff, Lennart; Lindstedt, Malin; Angell, Helen K.; Kim, Kyoung-Mee; Kim, Seung-Tae; Kim, Sung; Sharpe, Alan D.; Ogden, Julia; Davenport, Anna; Hodgson, Darren R.; Barrett, Carl; Lee, Jeeyun; Kilgour, Elaine; Hanson, Jodi; Caspell, Richard; Karulin, Alexey; Lehmann, Paul; Ansari, Tameem; Schiller, Annemarie; Sundararaman, Srividya; Roen, Diana; Ayers, Mark; Levitan, Diane; Arreaza, Gladys; Liu, Fang; Mogg, Robin; Bang, Yung-Jue; O’Neil, Bert; Cristescu, Razvan; Friedlander, Philip; Wassman, Karl; Kyi, Chrisann; Oh, William; Bhardwaj, Nina; Bornschlegl, Svetlana; Gustafson, Michael P.; Gastineau, Dennis A.; Parney, Ian F.; Dietz, Allan B.; Carvajal-Hausdorf, Daniel; Mani, Nikita; Schalper, Kurt; Rimm, David; Chang, Serena; Kurland, John; Ahlers, Christoph Matthias; Jure-Kunkel, Maria; Cohen, Lewis; Maecker, Holden; Kohrt, Holbrook; Chen, Shuming; Crabill, George; Pritchard, Theresa; McMiller, Tracee; Pardoll, Drew; Pan, Fan; Topalian, Suzanne; Danaher, Patrick; Warren, Sarah; Dennis, Lucas; White, Andrew M.; D’Amico, Leonard; Geller, Melissa; Disis, Mary L.; Beechem, Joseph; Odunsi, Kunle; Fling, Steven; Derakhshandeh, Roshanak; Webb, Tonya J.; Dubois, Sigrid; Conlon, Kevin; Bryant, Bonita; Hsu, Jennifer; Beltran, Nancy; Müller, Jürgen; Waldmann, Thomas; Duhen, Rebekka; Duhen, Thomas; Thompson, Lucas; Montler, Ryan; Weinberg, Andrew; Kates, Max; Early, Brandon; Yusko, Erik; Schreiber, Taylor H.; Bivalacqua, Trinity J.; Lunceford, Jared; Nebozhyn, Michael; Murphy, Erin; Loboda, Andrey; Kaufman, David R.; Albright, Andrew; Cheng, Jonathan; Kang, S. Peter; Shankaran, Veena; Piha-Paul, Sarina A.; Yearley, Jennifer; Seiwert, Tanguy; Ribas, Antoni; McClanahan, Terrill K.; Sher, Xinwei; Liu, Xiao Qiao; Joe, Andrew; Plimack, Elizabeth; Forrest-Hay, Alex; Guyre, Cheryl A.; Narumiya, Kohei; Delcommenne, Marc; Hirsch, Heather A.; Deshpande, Amit; Reeves, Jason; Shu, Jenny; Zi, Tong; Michaelson, Jennifer; Law, Debbie; Trehu, Elizabeth; Sathyanaryanan, Sriram; Hodkinson, Brendan P.; Hutnick, Natalie A.; Schaffer, Michael E.; Gormley, Michael; Hulett, Tyler; Ballesteros-Merino, Carmen; Dubay, Christopher; Afentoulis, Michael; Reddy, Ashok; David, Larry; Jayant, Kumar; Agrawal, Swati; Agrawal, Rajendra; Jeyakumar, Ghayathri; Kim, Seongho; Kim, Heejin; Silski, Cynthia; Suisham, Stacey; Heath, Elisabeth; Vaishampayan, Ulka; Vandeven, Natalie; Viller, Natasja Nielsen; O’Connor, Alison; Chen, Hui; Bossen, Bolette; Sievers, Eric; Uger, Robert; Johnson, Lisa; Kao, Hsiang-Fong; Hsiao, Chin-Fu; Lai, Shu-Chuan; Wang, Chun-Wei; Ko, Jenq-Yuh; Lou, Pei-Jen; Lee, Tsai-Jan; Liu, Tsang-Wu; Hong, Ruey-Long; Kearney, Staci J.; Black, Joshua C.; Landis, Benjamin J.; Koegler, Sally; Hirsch, Brooke; Gianani, Roberto; Kim, Jeffrey; He, Ming-Xiao; Zhang, Bingqing; Su, Nan; Luo, Yuling; Ma, Xiao-Jun; Park, Emily; Kim, Dae Won; Copploa, Domenico; Kothari, Nishi; doo Chang, Young; Kim, Richard; Kim, Namyong; Lye, Melvin; Wan, Ee; Knaus, Hanna A.; Berglund, Sofia; Hackl, Hubert; Karp, Judith E.; Gojo, Ivana; Luznik, Leo; Hong, Henoch S.; Koch, Sven D.; Scheel, Birgit; Gnad-Vogt, Ulrike; Kallen, Karl-Josef; Wiegand, Volker; Backert, Linus; Kohlbacher, Oliver; Hoerr, Ingmar; Fotin-Mleczek, Mariola; Billingsley, James M.; Koguchi, Yoshinobu; Conrad, Valerie; Miller, William; Gonzalez, Iliana; Poplonski, Tomasz; Meeuwsen, Tanisha; Howells-Ferreira, Ana; Rattray, Rogan; Campbell, Mary; Bifulco, Carlo; Bahjat, Keith; Curti, Brendan; Vetsika, E-K; Kallergi, G.; Aggouraki, Despoina; Lyristi, Z.; Katsarlinos, P.; Koinis, Filippos; Georgoulias, V.; Kotsakis, Athanasios; Martin, Nathan T.; Aeffner, Famke; Cerkovnik, Logan; Pratte, Luke; Kim, Rebecca; Krueger, Joseph; Martínez-Usatorre, Amaia; Jandus, Camilla; Donda, Alena; Carretero-Iglesia, Laura; Speiser, Daniel E.; Zehn, Dietmar; Rufer, Nathalie; Romero, Pedro; Panda, Anshuman; Mehnert, Janice; Hirshfield, Kim M.; Riedlinger, Greg; Damare, Sherri; Saunders, Tracie; Sokol, Levi; Stein, Mark; Poplin, Elizabeth; Rodriguez-Rodriguez, Lorna; Silk, Ann; Chan, Nancy; Frankel, Melissa; Kane, Michael; Malhotra, Jyoti; Aisner, Joseph; Kaufman, Howard L.; Ali, Siraj; Ross, Jeffrey; White, Eileen; Bhanot, Gyan; Ganesan, Shridar; Monette, Anne; Bergeron, Derek; Amor, Amira Ben; Meunier, Liliane; Caron, Christine; Morou, Antigoni; Kaufmann, Daniel; Liberman, Moishe; Jurisica, Igor; Mes-Masson, Anne-Marie; Hamzaoui, Kamel; Lapointe, Rejean; Mongan, Ann; Ku, Yuan-Chieh; Tom, Warren; Sun, Yongming; Pankov, Alex; Looney, Tim; Au-Young, Janice; Hyland, Fiona; Conroy, Jeff; Morrison, Carl; Glenn, Sean; Burgher, Blake; Ji, He; Gardner, Mark; Omilian, Angela R.; Bshara, Wiam; Angela, Omilian; Obeid, Joseph M.; Erdag, Gulsun; Smolkin, Mark E.; Deacon, Donna H.; Patterson, James W.; Chen, Lieping; Bullock, Timothy N.; Slingluff, Craig L.; Loffredo, John T.; Vuyyuru, Raja; Beyer, Sophie; Spires, Vanessa M.; Fox, Maxine; Ehrmann, Jon M.; Taylor, Katrina A.; Korman, Alan J.; Graziano, Robert F.; Page, David; Sanchez, Katherine; Martel, Maritza; De Macedo, Mariana Petaccia; Qin, Yong; Reuben, Alex; Spencer, Christine; Guindani, Michele; Racolta, Adriana; Kelly, Brian; Jones, Tobin; Polaske, Nathan; Theiss, Noah; Robida, Mark; Meridew, Jeffrey; Habensus, Iva; Zhang, Liping; Pestic-Dragovich, Lidija; Tang, Lei; Sullivan, Ryan; Olencki, Thomas; Hutson, Thomas; Roder, Joanna; Blackmon, Shauna; Roder, Heinrich; Stewart, John; Amin, Asim; Ernstoff, Marc S.; Clark, Joseph I.; Atkins, Michael B.; Sosman, Jeffrey; McDermott, David; Kluger, Harriet; Halaban, Ruth; Snzol, Mario; Asmellash, Senait; Steingrimsson, Arni; Wang, Chichung; Roman, Kristin; Clement, Amanda; Downing, Sean; Hoyt, Clifford; Harder, Nathalie; Schmidt, Guenter; Schoenmeyer, Ralf; Brieu, Nicolas; Yigitsoy, Mehmet; Madonna, Gabriele; Botti, Gerardo; Grimaldi, Antonio; Ascierto, Paolo A.; Huss, Ralf; Athelogou, Maria; Hessel, Harald; Buchner, Alexander; Stief, Christian; Binnig, Gerd; Kirchner, Thomas; Sellappan, Shankar; Thyparambil, Sheeno; Schwartz, Sarit; Cecchi, Fabiola; Nguyen, Andrew; Vaske, Charles; Hembrough, Todd; Spacek, Jan; Vocka, Michal; Zavadova, Eva; Skalova, Helena; Dundr, Pavel; Petruzelka, Lubos; Francis, Nicole; Tilman, Rau T.; Hartmann, Arndt; Netikova, Irena; Stump, Julia; Tufman, Amanda; Berger, Frank; Neuberger, Michael; Hatz, Rudolf; Lindner, Michael; Sanborn, Rachel E.; Handy, John; Huber, Rudolf M.; Winter, Hauke; Reu, Simone; Sun, Cheng; Xiao, Weihua; Tian, Zhigang; Arora, Kshitij S.; Desai, Niyati; Kulkarni, Anupriya; Rajurkar, Mihir; Rivera, Miguel; Deshpande, Vikram; Ting, David; Tsai, Katy; Nosrati, Adi; Goldinger, Simone; Hamid, Omid; Algazi, Alain; Tumeh, Paul; Hwang, Jimmy; Liu, Jacqueline; Chen, Lawrence; Dummer, Reinhard; Rosenblum, Michael; Daud, Adil; Tsao, Tsu-Shuen; Ashworth-Sharpe, Julia; Johnson, Donald; Bhaumik, Srabani; Bieniarz, Christopher; Couto, Joseph; Farrell, Michael; Ghaffari, Mahsa; Hubbard, Antony; Kosmeder, Jerome; Lee, Cleo; Marner, Erin; Uribe, Diana; Zhang, Hongjun; Zhang, Jian; Zhang, Wenjun; Zhu, Yifei; Morrison, Larry; Tsujikawa, Takahiro; Borkar, Rohan N.; Azimi, Vahid; Kumar, Sushil; Thibault, Guillaume; Mori, Motomi; El Rassi, Edward; Clayburgh, Daniel R.; Kulesz-Martin, Molly F.; Flint, Paul W.; Coussens, Lisa M.; Villabona, Lisa; Masucci, Giuseppe V.; Geiss, Gary; Birditt, Brian; Mei, Qian; Huang, Alan; Eagan, Maribeth A.; Ignacio, Eduardo; Elliott, Nathan; Dunaway, Dwayne; Jung, Jaemyeong; Merritt, Chris; Sprague, Isaac; Webster, Philippa; Liang, Yan; Wenthe, Jessica; Enblad, Gunilla; Karlsson, Hannah; Essand, Magnus; Savoldo, Barbara; Dotti, Gianpietro; Höglund, Martin; Brenner, Malcolm K.; Hagberg, Hans; Loskog, Angelica; Bernett, Matthew J.; Moore, Gregory L.; Hedvat, Michael; Bonzon, Christine; Chu, Seung; Rashid, Rumana; Avery, Kendra N.; Muchhal, Umesh; Desjarlais, John; Kraman, Matthew; Kmiecik, Katarzyna; Allen, Natalie; Faroudi, Mustapha; Zimarino, Carlo; Wydro, Mateusz; Doody, Jacqueline; Srinivasa, Sreesha P.; Govindappa, Nagaraja; Reddy, Praveen; Dubey, Aparajita; Periyasamy, Sankar; Adekandi, Madhukara; Dey, Chaitali; Joy, Mary; van Loo, Pieter Fokko; Veninga, Henrike; Shamsili, Setareh; Throsby, Mark; Dolstra, Harry; Bakker, Lex; Alva, Ajjai; Gschwendt, Juergen; Loriot, Yohann; Bellmunt, Joaquim; Feng, Dai; Poehlein, Christian; Powles, Thomas; Antonarakis, Emmanuel S.; Drake, Charles G.; Wu, Haiyan; De Bono, Johann; Bannerji, Rajat; Byrd, John; Gregory, Gareth; Opat, Stephen; Shortt, Jake; Yee, Andrew; Raje, Noopur; Thompson, Seth; Balakumaran, Arun; Kumar, Shaji; Rini, Brian I.; Choueiri, Toni; Mariani, Mariangela; Albiges, Laurence; Haanen, John B.; Larkin, James; Schmidinger, Manuela; Magazzù, Domenico; di Pietro, Alessandra; Motzer, Robert J.; Borch, Troels Holz; Kongsted, Per; Pedersen, Magnus; Met, Özcan; Boudadi, Karim; Wang, Hao; Vasselli, James; Baughman, Jan E.; Wigginton, Jon; Abdallah, Rehab; Ross, Ashley; Park, Jiwon; Grossenbacher, Steven; Luna, Jesus I.; Withers, Sita; Culp, William; Chen, Mingyi; Monjazeb, Arta; Kent, Michael S.; Chandran, Smita; Danforth, David; Yang, James; Klebanoff, Christopher; Goff, Stephanie; Paria, Biman; Sabesan, Arvind; Srivastava, Abhishek; Kammula, Udai; Richards, Jon; Faries, Mark; Andtbacka, Robert H. 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Regulation of T Cell Differentiation and Function by EZH2
(Frontiers Media S.A., 2016) Karantanos, Theodoros; Chistofides, Anthos; Barhdan, Kankana; Li, Lequn; Boussiotis, Vassiliki
The enhancer of zeste homolog 2 (EZH2), one of the polycomb-group proteins, is the catalytic subunit of Polycomb-repressive complex 2 (PRC2) and induces the trimethylation of the histone H3 lysine 27 (H3K27me3) promoting epigenetic gene silencing. EZH2 contains a SET domain promoting the methyltransferase activity, while the three other protein components of PRC2, namely EED, SUZ12, and RpAp46/48, induce compaction of the chromatin permitting EZH2 enzymatic activity. Numerous studies highlight the role of this evolutionary conserved protein as a master regulator of differentiation in humans involved in the repression of the homeotic gene and the inactivation of X-chromosome. Through its effects in the epigenetic regulation of critical genes, EZH2 has been strongly linked to cell cycle progression, stem cell pluripotency, and cancer biology, being currently at the cutting edge of research. Most recently, EZH2 has been associated with hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis. Several studies have evaluated the role of EZH2 in the regulation of T cell differentiation and plasticity as well as its implications in the development of autoimmune diseases and graft-versus-host disease (GVHD). The aim of this review is to summarize the current knowledge regarding the role of EZH2 in the regulation of the differentiation and function of T cells focusing on possible applications in various immune-mediated conditions, including autoimmune disorders and GVHD.
PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation
(Nature Pub. Group, 2015) Patsoukis, Nikolaos; Bardhan, Kankana; Chatterjee, Pranam; Sari, Duygu; Liu, Bianling; Bell, Lauren N.; Karoly, Edward D.; Freeman, Gordon J.; Petkova, Victoria; Seth, Pankaj; Li, Lequn; Boussiotis, Vassiliki
During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade.
Corrigendum: Regulation of T Cell Differentiation and Function by EZH2
(Frontiers Media S.A., 2016) Karantanos, Theodoros; Christofides, Anthos; Bardhan, Kankana; Li, Lequn; Boussiotis, Vassiliki
Immunometabolic Regulations Mediated by Coinhibitory Receptors and Their Impact on T Cell Immune Responses
(Frontiers Media S.A., 2017) Patsoukis, Nikolaos; Weaver, Jessica D.; Strauss, Laura; Herbel, Christoph; Seth, Pankaj; Boussiotis, Vassiliki
Host immunity provides wide spectrum protection that serves to eradicate pathogens and cancer cells, while maintaining self-tolerance and immunological homeostasis. Ligation of the T cell receptor (TCR) by antigen activates signaling pathways that coordinately induce aerobic glycolysis, mitochondrial activity, anabolic metabolism, and T effector cell differentiation. Activation of PI3K, Akt, and mTOR triggers the switch to anabolic metabolism by inducing transcription factors such as Myc and HIF1, and the glucose transporter Glut1, which is pivotal for the increase of glucose uptake after T cell activation. Activation of MAPK signaling is required for glucose and glutamine utilization, whereas activation of AMPK is critical for energy balance and metabolic fitness of T effector and memory cells. Coinhibitory receptors target TCR-proximal signaling and generation of second messengers. Imbalanced activation of such signaling pathways leads to diminished rates of aerobic glycolysis and impaired mitochondrial function resulting in defective anabolic metabolism and altered T cell differentiation. The coinhibitory receptors mediate distinct and synergistic effects on the activation of signaling pathways thereby modifying metabolic programs of activated T cells and resulting in altered immune functions. Understanding and therapeutic targeting of metabolic programs impacted by coinhibitory receptors might have significant clinical implications for the treatment of chronic infections, cancer, and autoimmune diseases.
Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector
(The Rockefeller University Press, 2012) Wynne, Joseph P.; Wu, Jinhua; Su, Wenjuan; Mor, Adam; Patsoukis, Nikolaos; Boussiotis, Vassiliki; Hubbard, Stevan R.; Philips, Mark R.
Adaptive immunity depends on lymphocyte adhesion that is mediated by the integrin lymphocyte functional antigen 1 (LFA-1). The small guanosine triphosphatase Rap1 regulates LFA-1 adhesiveness through one of its effectors, Rap1-interacting adapter molecule (RIAM). We show that RIAM was recruited to the lymphocyte plasma membrane (PM) through its Ras association (RA) and pleckstrin homology (PH) domains, both of which were required for lymphocyte adhesion. The N terminus of RIAM inhibited membrane translocation. In vitro, the RA domain bound both Rap1 and H-Ras with equal but relatively low affinity, whereas in vivo only Rap1 was required for PM association. The PH domain bound phosphoinositol 4,5-bisphosphate (PI(4,5)P2) and was responsible for the spatial distribution of RIAM only at the PM of activated T cells. We determined the crystal structure of the RA and PH domains and found that, despite an intervening linker of 50 aa, the two domains were integrated into a single structural unit, which was critical for proper localization to the PM. Thus, the RA-PH domains of RIAM function as a proximity detector for activated Rap1 and PI(4,5)P2.