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1. Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors

Author

Jian Ding, Sarah Guyette, Brett Schrand, Jessica Geirut, Holly Horton, Guangwu Guo, Greg Delgoffe, Ashley Menk, Patrick A. Baeuerle, Robert Hofmeister, and Robert Tighe

Subjects
Chimeric antigen receptor, mesothelin, metabolism, T cell receptor, T cell Receptor Fusion Construct (TRuC®) T cells, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

ABSTRACTT cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.

Published
2023
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14. Challenges and next steps in the advancement of immunotherapy: summary of the 2018 and 2020 National Cancer Institute workshops on cell-based immunotherapy for solid tumors

Author

Nirali Shah, Lili Yang, Anju Singh, Kasia Bourcier, Antoni Ribas, Pawel Kalinski, Ke Liu, Phil Greenberg, Carl June, Marcela Maus, Steven Rosenberg, Madhav Dhodapkar, Irina Tiper, Chantale Bernatchez, Michael Hudecek, Stanley Riddell, Stephen Gottschalk, Crystal Mackall, Lisa Butterfield, Greg Delgoffe, Michael Nishimura, Terry Fry, Marc S. Ernstoff, Christopher Klebanoff, Elad Sharon, Malcolm Brenner, Cliona Rooney, Christine Brown, Marc S Ernstoff, Tonya Webb, Magdalena Thurin, Wendell Lim, David Stroncek, Catherine Bollard, Helen Chen, Cameron Turtle, Christian Hinrichs, Laura K Fogli, Rosemarie Aurigemma, Connie L Sommers, Steven Albelda, Renier Brentjens, Yvonne Chen, Laronna Colbert, Kenneth Cornetta, Jason Cristofaro, Thomas Finn, Laura K Fogli Hunter, Alyssa Galaro, Ananda Goldrath, Ray Harris, Lori Henderson, Yuxia Jia, Dan Kaufman, Bruce Levine, Lawrence Lum, Samantha Maragh, Alex Marson, Raj Puri, Jake Reder, Kole Roybal, Rachelle Salomon, Tal Salz, Barbra Sasu, Andrea Schietinger, Connie L. Sommers, Minkyung Song, Fyodor Urnov, Anthony Welch, Travis Young, and Jason Yovandich

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Cell-based immunotherapies have had remarkable success in the clinic, specifically in the treatment of hematologic malignancies. However, these strategies have had limited efficacy in patients with solid tumors. To better understand the challenges involved, the National Cancer Institute (NCI) convened an initial workshop with immuno-oncology thought leaders in December 2018 and a follow-up workshop in December 2020. The goals of the NCI workshops on cell-based immunotherapy for solid tumors were to discuss the current state of the field of cell-based immunotherapy, obtain insights into critical knowledge gaps, and identify ways in which NCI could facilitate progress. At both meetings, subjects emphasized four main types of challenges in further developing cell-based immunotherapy for patients with solid tumors: scientific, technical, clinical, and regulatory. The scientific barriers include selecting appropriate targets, ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor microenvironment, and identifying appropriate models for these investigations. While mouse models may provide some useful data, the majority of those that are commonly used are immunodeficient and unable to fully recapitulate the immune response in patients. There is therefore a need for enhanced support of small early-phase human clinical studies, preferably with adaptive trial designs, to provide proof of concept for novel cell therapy approaches. Furthermore, the requirements for manufacturing, shipping, and distributing cell-based therapies present technical challenges and regulatory questions, which many research institutions are not equipped to address. Overall, workshop subjects identified key areas where NCI support might help the research community in driving forward innovation and clinical utility: 1) provide focused research support on topics such as tumor target selection, immune cell fitness and persistence, cell trafficking, and the immunosuppressive tumor microenvironment; 2) support the rapid translation of preclinical findings into proof of concept clinical testing, harmonize clinical trial regimens, and facilitate early trial data sharing (including negative results); 3) expand manufacturing support for cell therapies, including vectors and reagents, and provide training programs for technical staff; and 4) develop and share standard operating procedures for cell handling and analytical assays, and work with the Food and Drug Administration to harmonize product characterization specifications.

Published
2021
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15. 254 CTLA-4 blockade promotes Treg glucose metabolism and reduces Treg functional stability in glycolysis-defective tumors

Author

Yasin Senbabaoglu, Greg Delgoffe, Ping-Chih Ho, Arnab Ghosh, Svena Verma, McLane Watson, Inna Serganova, Ivan Cohen, Masatomo Maeda, Masahiro Shindo, Rachana Maniyar, Mayuresh Mane, Avigdor Leftin, Matthew Lubin, Myat Kyaw Ko, Mohsen Abu-Akeel, Ellen Ackerstaff, Jason Koutcher, and Ronald Blasberg

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2020
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24. EXCESS DIETARY SUGAR ALTERS COLONOCYTE METABOLISM AND IMPAIRS THE EARLY PROLIFERATIVE RESPONSE TO DAMAGE

Author

Ansen Burr, Junyi Ji, Kadir Ozler, Heather Mentrup, Onur Eskiocak, Rachel Cumberland, Ashley Menk, Xiaoyi Zhang, Abigail Overacre-Delgoffe, Natalie Rittenhouse, Chris Marshall, Vaughn Cooper, Amanda Poholek, Greg Delgoffe, Semir Beyaz, and Timothy Hand

Subjects
Hepatology, Gastroenterology, Immunology and Allergy
Abstract

The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. An important regulator of ISC and TA cell function is dietary metabolites which can affect their proliferative capacity. Over the last 150 years, the diet of high-income countries contains increasing amounts of simple sugars, such as sucrose, but whether excess sugar affects the function of ISCs and TA cells directly is unknown. We used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (DSS colitis) to demonstrate the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. We demonstrate that high sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative and key stem cell gene signatures. Further, high-glucose conditions led to the accumulation of glycolytic metabolite pyruvate in colonoids, with a concomitant decrease in ATP, suggesting impaired glycolytic fuel metabolism. Treatment of colonoids with DCA, which forces pyruvate into the TCA cycle, restored their growth, ATP levels, and the expression of proliferation and stem cell gene signatures. Similarly, DSS treatment of mice fed a high sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Metabolic analyses of crypt cells from high-sucrose-fed mice revealed increased glycolytic potential without a commensurate increase in aerobic respiration. Rather, epithelium from high-sucrose-fed mice has increased mitochondrial content, without increased levels of ATP, further demonstrating impaired oxidative phosphorylation and fuel metabolism. Finally, we demonstrated impaired proliferative potential of ISCs and reduced number of TA direct daughter cells in high-sucrose-fed mice with DSS damage. Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury, as is seen in patients with an acute flare of Ulcerative Colitis.

Published
2023

25. Tumor hypoxia drives suppressor function in exhausted T cells limiting antitumor immunity

Author

Greg Delgoffe, Paolo Vignali, Kristin DePeaux, McLane Watson, Konstantinos Lontos, Nicole McGaa, Nicole Scharping, and Ashley Menk

Abstract

While CD8+ cytotoxic T cells are clearly critical for identification and elimination of cancer cells, factors concentrated within the tumor microenvironment drive their altered differentiation to a hypofunctional, short-lived state termed exhaustion. Exhaustion is a progressive lineage, and it is now clear that the most terminally exhausted T (tTexh) cells are not the targets of checkpoint blockade immunotherapy but rather serve as factors that limit immunotherapeutic efficacy. Compared directly, tumor-infiltrating CD8+ tTexh cells bear notable phenotypic similarity to CD4+Foxp3+ regulatory T (Treg) cells, suggesting beyond loss of proinflammatory function, tTexh cells may be directly anti-functional and constrain tumor specific immunity. Here we show, when isolated from the same tumor microenvironment, terminally exhausted CD8+ T cells carried similar capacity to suppress T cell proliferation as CD4+Foxp3+ Treg cells. Unlike Treg cells, tTexh cells suppress solely via the ectonucleotidase CD39, which serves to deplete extracellular ATP (eATP) and produce an adenosinergic environment. CD39 expression in tTexh cells is driven by exposure to tumor hypoxia, such that therapeutic targeting of hypoxia limits tTexh suppression and support responses to immunotherapy. Specific deletion of CD39 in CD8+ T cells slows tumor progression and improves response to checkpoint blockade, highlighting a major role for immunosuppression by exhausted T cells in cancer. Thus, tTexh cells are an unappreciated immunoregulatory population and for full immunotherapeutic efficacy, strategies should be designed to either limit their generation, reprogram their immunosuppressive nature, or remove them from the tumor microenvironment.

Published
2021

26. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016

27. Lymphocyte activation gene-3 regulates mitochondrial biogenesis and metabolism of naive CD4+ T cells

Author

Previte, Dana Michelle, Menk, Ashley V., Wright, Rebecca H., Coudriet, Gina M., Greg Delgoffe, and Piganelli, Jon D.

Subjects
Immunology, Immunology and Allergy
Abstract

Lymphocyte Activation Gene-3 (LAG-3) is an inhibitory receptor expressed on the surface of various immune cells, including CD4+ T cells. While LAG-3 is more frequently associated with T cell exhaustion and regulatory T cells, it is also a negative regulator of T cell homeostatic expansion. Current interest in how cellular metabolism dictates immune cell function and fate has elucidated that CD4+ T cell function is tightly coupled to metabolism. Therefore, given that LAG-3 is a regulator of CD4+ T cell homeostatic expansion, and the ability to proliferate is highly dependent upon metabolism, we hypothesized that LAG-3 regulates the metabolic profile of naïve CD4+ T cells. Naive OT.II T cells were isolated from wildtype and LAG-3−/− animals, and analyzed by Seahorse Flux Analyzer. LAG-3−/− OT.II cells demonstrated significantly increased basal respiration, spare respiratory capacity, and aerobic glycolysis, as compared to wildtype OT.IIs, indicating an enhanced metabolic profile. Further analysis indicated that LAG-3-deficient OT.IIs displayed increased mitochondrial biogenesis via enhanced signaling through the AMPK/Sirt-1 pathway. In an adoptive transfer model of homeostatic expansion, LAG-3−/− OT.II cells expanded to a greater extent and continued to demonstrate an enhanced metabolic profile as compared to WT OT.IIs. This proved to be extrinsically regulated, as LAG-3 blockade in WT recipients recapitulated similar results to LAG-3−/− T cells. These results demonstrate that LAG-3 is critical for actively maintaining metabolic quiescence in naïve CD4+ T cells. Future directions include investigating the influence of LAG-3 and its metabolic regulation in the context of autoimmunity.

Published
2017

28. Neuropilin-1 enforces Treg stability and function in the tumor microenvironment. (TUM2P.889)

Author

Abigail Overacre, Greg Delgoffe, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) play an integral role in the adaptive immune system by suppressing detrimental self-reactive responses. However, Tregs have deleterious effects in cancer through suppression of the anti-tumor immune response. Therefore, it is advantageous to understand the role of Tregs in the tumor microenvironment in order to create targeted cancer therapies. Our lab has uncovered a novel function for neuropilin-1 (Nrp1) on Tregs in tumors. In the absence of Nrp1 ligation by its ligand, Sema4a, Tregs lose stability and suppressive capabilities, leading to enhanced anti-tumor immunity and reduced tumor growth or tumor clearance. We hypothesize that the loss of Nrp1 expression on Tregs reduces intratumoral stability through altered intracellular pathways and diminished Foxp3 expression, transforming Tregs from an anti-inflammatory to a pro-inflammatory T cell population. Nrp1-deficient Tregs have a hypermethylated Foxp3 CNS2/TSDR locus in the tumor microenvironment, comparable to Teff, and display TH1-like characteristics, with upregulation of Tbet, CXCR3, and IFNγ, and the reduction of suppressive molecules, IL-10 and CD73. Furthermore, in competitive environments Nrp1-deficient Tregs undermine and limit the function of wild-type Tregs. Further mechanistic analysis and fate mapping studies will elucidate the cell-intrinsic and cell-extrinsic impact of Nrp1 loss on Treg function and tumor clearance.

Published
2014

29. IL35 neutralization enhances tumor specific immunity in mouse models of cancer (P2024)

Author

Meghan Turnis, David Gravano, Greg Delgoffe, Heidi Steinkamp, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Treg) are critical to maintenance of self-tolerance and prevention of autoimmunity; however, they also function to limit anti-cancer responses.Therefore, clarifying the mechanisms of Treg-mediated suppression in the context of cancer will aid in the rational design of new therapies.Our lab has identified a novel suppressive role for the IL35 heterodimer in Treg. IL35 is a member of the IL12 family composed of IL12a and Ebi3 subunits and is preferentially expressed by Treg. Treg and other suppressive factors in the tumor microenvironment inhibit antigen-specific cytotoxic lymphocyte responses; depletion or inhibition of Treg has been shown to decrease tumor burden and enhance patient outcome in both animal models and the clinic. We hypothesize that IL35 contributes critically to the tumor microenvironment and that its elimination will enhance tumor specific immunity. Using neutralizing antibodies specific for IL35-Ebi3, we have shown that systemic neutralization of IL35 significantly slows tumor growth compared with IgG control and enhances survival in the B16 melanoma model. Molecular analysis of tumor-infiltrating lymphocytes (TILs) has shown increased numbers, more activated CD8+ cells (CD44+CD62L-), and a greater proportion of proliferative cells by BrdU/Ki-67 staining in IL35-neutralized animals. We are currently extending studies to include metastatic and genetic models to better understand the mechanism of IL35 activity in the tumor microenvironment.

Published
2013

30. Potentiation of regulatory T cell stability and function via a neuropilin-1:semaphorin-4a axis (P1057)

Author

Greg Delgoffe, Seng Woo, Meghan Turnis, David Gravano, Cliff Guy, Matthew Bettini, David Finkelstein, Peter Vogel, Jody Bonnevier, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells represent a critical immunoregulatory component of the immune system. The signals that maintain Treg stability and potentiate their function remain obscure. Here we show that the immune cell surface ligand semaphorin-4a on conventional murine and human T cells and dendritic cells interacts with the Treg-restricted receptor neuropilin-1 to potentiate Treg function and enhance survival. Mice with a Treg-restricted deletion of Nrp1 exhibit extremely limited tumor-induced tolerance, and thus substantial resistance to certain tumors, yet do not develop any autoimmune or inflammatory manifestations. Sema4a or Nrp1 blockade also had therapeutic efficacy against pre-existing tumors. In addition, Nrp1-deficient Treg cells fail to suppress inflammatory colitis. Upon Sema4a ligation, Nrp1 was recruited to the immunological synapse and repressed Akt activity via PTEN, which facilitated Foxo nuclear translocation. This induced a transcriptional program that promoted Treg stability, survival and function while repressing the induction of lineage-specific transcription factors. Thus, Nrp1 ligation enforces Treg stability and function in highly inflammatory sites but is dispensable for the maintenance of immune homeostasis, highlighting Nrp1 as a potential immunotherapeutic target in cancer.

Published
2013

31. Exosomes represent a novel mechanism of regulatory T cell suppression (P1079)

Author

Heidi Steinkamp, Greg Delgoffe, Sharon Frase, Ashley Castellaw, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells suppress via a variety of mechanisms, both contact-dependent and -independent mechanisms. These is some controversy as to which mechanisms play more dominant roles during various disease states as well as maintenance of immune homeostasis. Our laboratory has found that regulatory T cells secrete exosome-like vesicles that are 20 to 50 nm in diameter. Membrane vesicles have been shown to mediate communication amongst immune cells, but they also mediate communication between immune cells and cancer cells and between and immune cells and pathogens. Membrane vesicles mediate physiologic changes in recipient cells by initiating cellular signaling events following receptor binding, or via uptake and integration of vesicular cargo, which can include receptors, enzymes, cytokines, chemokines and genetic material. We have found that functional regulatory T cell membrane vesicles mediate suppression of conventional CD4+ T cells, whereas resting regulatory T cell and conventional T cell vesicles do not. Furthermore, we have found that 293F cells package overexpressed immunosuppressive cytokines into exosomes following transfection. Taken together these data suggest that exosome-like vesicles represent a bridge between contact dependent and independent regulatory T cell suppression.

Published
2013

32. The asymmetric partitioning of mTORC1 activity during cell division facilitates CD8+ effector versus memory T cell generation (110.18)

Author

Kristen Pollizzi, Greg Delgoffe, Ying-Chun Lo, Chirag Patel, and Jonathan Powell

Subjects
Immunology, Immunology and Allergy
Abstract

CD8+ T cells are an essential component of the adaptive immune response, generating both effector cells necessary for clearance of acute infection and long-lived memory cells primed to provide a rapid response upon secondary infection. The mechanism by which CD8+ T cell effector versus memory differentiation arises remains unclear. Here we show that upon antigen stimulation, mTORC1 activity is asymmetrically partitioned during cell division. Cells fated to become effector cells show high mTORC1 activity, while memory precursors have low mTORC1 signaling. These results correlate with experiments generated from T cell specific knockouts of Rheb, an mTORC1 activator, and TSC2, an mTORC1 negative regulator. CD8+ T cells deficient in mTORC1 activity fail to differentiate into effector cells, but retain memory characteristics such as surface marker expression and longevity in vivo. In contrast, CD8+ T cells with hyper-active mTORC1 signaling have potent effector capabilities both in vitro and in vivo but retain the phenotype of terminally differentiated effector cells incapable of transitioning into memory, being short lived and unable to proliferate upon secondary infection. Our data highlight a role of mTOR as a critical regulator in determining CD8+ T cell fate. Further, we suggest that the generation of CD8+ T cell effector vs. memory lineages is dependent upon the asymmetric distribution of mTORC1 signaling during cell division.

Published
2012

33. Defining the role of mTOR in effector and memory CD8+ T cell differentiation (46.20)

Author

Kristen Pollizzi, Greg Delgoffe, Adam Waickman, and Jonathan Powell

Subjects
Immunology, Immunology and Allergy
Abstract

Recent studies implicate mTOR in the generation of CD8+ T cell memory. Here, we demonstrate that mTORC1 is required for CD8+ T cell effector function during the activation of naïve CD8+ T cells. We generated mouse T cell-specific knockouts of Rheb, a TORC1 component; TSC2, a TORC1 negative regulator; and Rictor, a TORC2 component. We show both in vivo and in vitro that Rheb-/- CD8+ T cells have diminished effector capabilities, specifically reduced cytokine secretion and proliferation after stimulation or infection. However, these cells persist for over 30 days and retain memory cell characteristics. Conversely, TSC2-/- antigen-specific CD8+ T cells display robust effector function with increased proliferation and cytokine secretion relative to wildtype (WT). The majority of these TSC2-\- cells are unable to transition to a memory phenotype and perish during the contraction phase. Interestingly, TORC2 is not required for effector function as Rictor-/- CD8+T cells are capable of cytokine secretion and proliferation during a primary immune response. Loss of TORC2 may in fact promote memory responses, as we found Rictor-/- CD8+ T cells to have more potent antigen recall in adoptive transfer compared to WT cells. We use this novel approach to selectively probe specific mTOR functions in T cells. Ultimately, our findings highlight the divergent roles of TORC1 and TORC2 in directing CD8+ T cell effector and memory function.

Published
2011

34. TSC2 regulates CD8+ T cell effector function and the generation of memory (132.14)

Author

Kristen Pollizzi, Adam Waickman, Greg Delgoffe, and Jonathan Powell

Subjects
Immunology, Immunology and Allergy
Abstract

Recent studies implicate mTOR activity in the generation of memory CD8+ T cells. Tuberous Sclerosis Complex 2 gene (TSC2) is an upstream inhibitor of mTOR function. In this report, mice in which TSC2 is deleted in T cells were utilized to determine the role of TSC2 in controlling T cell function. TSC2-/- T cells demonstrate enhanced and constitutive mTOR Complex 1 (TORC1) activity. Using a recombinant vaccinia virus expressing OVA peptide (vac-OVA) as the primary stimulation we have found that loss of TSC2 promotes an enhanced effector response in CD8+ T cells in terms of killing ability and cytokine production 7 days after injection. However, when assessing function at 30 days post-infection the absolute number of OVA specific CD8+ T cells are reduced compared to wildtype controls. This correlated with diminished killing ability as shown by in-vivo CTL activity. Interestingly, when the TSC2-/- OVA specific CD8+ T cells were analyzed at day 30 for cytokine production, these cells secreted increased IFNγ and TNFα over their Wt counterparts. Together these data indicate that TSC2 deficiency impairs the effector to memory transition. However, the absence of TSC2 leads to enhanced CD8+ effector function during the primary immune response and in the remaining clonotypic CD8+ T cells that are present 30 days post infection. Overall, our findings implicate a novel and complex role for TSC2 signaling in the regulation of both CD8+ T cell effector function and memory generation.

Published
2010

35. TORC1 and TORC2 selectively regulate CD4+ T helper cell lineage differentiation (50.35)

Author

Greg Delgoffe, Adam Waickman, Kristen Pollizzi, Bo Xiao, Paul Worley, and Jonathan Powell

Subjects
Immunology, Immunology and Allergy
Abstract

The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase that regulates cell division, survival, and translation. Downstream mTOR signals via two functionally distinct complexes, TORC1 and TORC2. We have previously shown T cells deficient in mTOR fail to differentiate into Th1, Th2, or Th17 cells and instead become Foxp3+ regulatory cells. We further dissected mTOR signaling in T cell differentiation by deleting Rheb (the activator of TORC1) and rictor (an essential TORC2 subunit). T cells lacking Rheb selectively lack TORC1 activity, and, like mTOR mutants, fail to differentiate into Th1 or Th17 cells when skewed. However, Rheb-deficient T cells retain their ability to become Th2 cells. This is due in part to diminished STAT4 and STAT3 activation, but elevated STAT6 activation. Alternatively, rictor-deficient cells specifically lack TORC2 activity, and fail to become Th2 cells when skewed. However, they retain the ability to become Th1 and Th17 cells, with a pattern of STAT activation that inversely correlates with TORC1 mutants. Interestingly, neither TORC1 nor TORC2 deficiency alone is sufficient to induce Treg differentiation. In vivo, TORC1 deficiency protects against EAE while TORC2 deficiency leads to accelerated disease. Our data support a novel paradigm in which TCR engagement in the absence of mTOR defaults to a regulatory fate, and TORC1 and TORC2 activation selectively regulate T cell effector lineage differentiation.

Published
2010

37. The role of LPC and lipid transporter MFSD2A in CD8 T cells

Author

Piccirillo, Ann, Hawse, William F., Menk, Ashley V., Wallace, Callen T., Buechel, Heather M., Watkins, Simon, Wendell, Stacy G., Greg Delgoffe, Silver, David L., and D Cruz, Louise M.

Subjects
Immunology, Immunology and Allergy
Abstract

Little is known about how effector CD8 T cells obtain exogenous long chain fatty acids (LCFAs) during T cell activation. LCFAs assist with membrane biogenesis and are required for rapid proliferation as well as effector molecule generation. One potential mechanism of fatty acid import is in the form of lysophophatidylcholine (LPC) by lipid carrier major facilitator superfamily domain containing 2a (MFSD2A). Here, we show that MFSD2A is highly expressed in activated CD8 T cells. Conditional loss of MFSD2A caused an altered effector response and resulted in defective memory cell formation. Taken together, these data show MFSD2A and LPC play a role in CD8 T cell metabolomics. Our future studies will use mass spectrometry lipidomics and gene expression analysis to identify the mechanisms by which CD8 T cells use LCFAs to mount a robust immune response to infection.

38. The lysophosphatidylcholine transporter, MFSD2A, is essential for CD8(+) memory T cell maintenance and secondary response to infection

Author

D Cruz, Louise M., Piccirillo, Ann, Hyzny, Eric, Menk, Ashley, Wallace, Callen, Hawse, William F., Buechel, Heather Marie, Wong, Bernice, Foo, Juat Chin, Cazenave-Gassiot, Amaury, Wenk, Markus, Greg Delgoffe, Watkins, Simon, and Silver, David

Subjects
Immunology, Immunology and Allergy
Abstract

Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous fatty acids has remained enigmatic. Here we discovered the sodium-dependent lysophosphatidylcholine transporter, Major Facilitator Super Family Domain Containing 2a (MFSD2A), is upregulated on activated CD8+ T cells and is required for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of lysophosphatidylcholine (LPC) esterified to long chain fatty acids (LCFAs) into activated CD8+ T cells, and MFSD2A deficient cells are at a competitive disadvantage resulting in reduced memory T cell formation and maintenance and reduced response to secondary infection. Mechanistically, import of LPCs was required to maintain T cell homeostatic turnover, that when lost resulted in a decreased memory T cell pool and thus a reduced secondary response to repeat infection.

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