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1. Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

Author

Elizabeth Repasky, Harry D Bear, Fang Yuan, Xiaofei Yu, Wenjie Liu, Shixian Chen, Xueqian Cheng, Patrick A Paez, Tuanwei Sun, Chunyan Wei, Joseph W Landry, Andrew S Poklepovic, John R Subjeck, Chunqing Guo, and Xiang-Yang Wang

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

Background The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.Methods Multiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170.Results Intratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8+ T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses.Conclusion Our results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance.

Published
2021
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2. New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

Author

Scott Gerber, Taylor Uccello, Maggie Lesch, Sarah Kintzel, Lauren Gradzewicz, Lillia Lamrous, Shawn Murphy, Fergal Fleming, Bradley Mills, Joseph Murphy, Angela Hughson, Jesse Garrett-Larsen, Haoming Qiu, Michael Drage, Jian Ye, Nicholas Gavras, David Keeley, Tanzy Love, Elizabeth Repasky, Edith Lord, and David Linehan

Abstract

Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

Published
2023
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3. The XIth International Online Symposium on Heat Shock Proteins in Biology and Medicine

Author

Stuart K, Calderwood, Elizabeth, Repasky, Len, Neckers, and Lawrence, Hightower

Subjects
Neoplasms, Humans, Medicine, Cell Biology, Biology, Meeting Review, Biochemistry, Heat-Shock Proteins, Heat-Shock Response
Abstract

Single cell and multicellular organisms encounter physical stress from their environment as well as behavioral stress experienced in more complex organisms. As these stresses can present an existential threat, organisms respond with a coordinated response at the tissue and cellular level, the heat shock response (HSR) and this was the major theme of the symposium. Much of the meeting was concentrated on the heat shock proteins (HSPs), the effector molecules of the response. The balance between the potency of the HSR and the experience of stress naturally plays a key role in the etiology of many disease. Roles in cancer, the immune response, cell metabolism and aging were discussed at length at the meeting. Finally, a major goal of this field is to enhance the HSR in pathological conditions where it becomes inadequate or over stimulated and important findings regarding pharmacological approaches to modulating the HSR were discussed.

Published
2022
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4. Impact of Environmental Temperature on the Pathological Complete Response and Survival Outcomes of Breast Cancer: A NCDB and SEER study

Author

Ashish Gupta, Kush Gupta, Arya Mariam Roy, Kristopher Attwood, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, Song Yao, and Shipra Gandhi

Abstract

Background: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate with an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates have higher odds of achieving pathologic complete response (pCR) and better survival outcomes than patients living in colder climates. Methods: A retrospective population-based analysis was conducted on Stage I-III breast cancer patients utilizing data from National Cancer Database (NCDB) from 2010-2018 with 892,092 patients and Surveillance, Epidemiology and End Results (SEER) from 1996-2017 with 270,496 patients. The average annual temperature (AAT) was calculated based on data from the National Centers for Environmental Information. Results: In the SEER cohort, patients residing at AAT ≥47.5°F had a 16% higher overall survival (OS) (HR 0.84, 95% CI 0.81- 0.88, p Conclusions: Higher environmental temperatures are associated with significantly better OS and DSS, as well as higher odds of achieving pCR in these patients. Future research is warranted to confirm this observation using large datasets, to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Published
2023
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5. Recombinant human Hsp110-gp100 chaperone complex vaccine is nontoxic and induces response in advanced stage melanoma patients

Author

Michael M. Wach, John R. Subjeck, Xiang-Yang Wang, Elizabeth Repasky, Junko Matsuzaki, Han Yu, Chong Wang, Daniel Fisher, Joseph J. Skitzki, and John M. Kane

Subjects
Male, Cancer Research, Skin Neoplasms, Dermatology, CD8-Positive T-Lymphocytes, Cancer Vaccines, Article, Mice, Oncology, Animals, Humans, Female, Melanoma, Aged, gp100 Melanoma Antigen
Abstract

Heat shock proteins (hsp) are intracellular chaperones that possess extracellular immunostimulatory properties when complexed with antigens. A recombinant Hsp110-gp100 chaperone complex vaccine showed an antitumor response and prolonged survival in murine melanoma. A phase Ib dose-escalation study of a recombinant human Hsp110-gp100 vaccine in advanced-stage melanoma patients was performed to evaluate toxicity, immunostimulatory potential and clinical response. Patients with pretreated, unresectable stage IIIB/C/IV melanoma received the chaperone complex vaccine in a dose-escalation protocol; three vaccinations over a 43-day-period. Tumor response, clinical toxicity and immune response were measured. Ten patients (eight female, median age 70 years) were enrolled and two patients had grade 1 adverse events; minor skin rash, hyperhidrosis and fever (no grade 2 or higher adverse events). Median progression-free survival was longer for lower vaccine doses as compared to the maximum dose of 180 mcg (4.5 vs. 2.9 months; P = 0.018). The lowest dose patients (30 and 60 mcg) had clinical tumor responses (one partial response, one stable disease). CD8+ T cell interferon-γ responses to gp100 were greater in the clinically responding patients. A pattern of B cell responses to vaccination was not observed. Regulatory T cell populations and co-stimulatory molecules including cytotoxic T-lymphocyte-associated protein 4 and PD-1 appeared to differ in responders versus nonresponders. A fully recombinant human Hsp110-gp100 chaperone complex vaccine had minimal toxicity, measurable tumor responses at lower doses and produced peripheral CD8+ T cell activation in patients with advanced, pretreated melanoma. Combination with currently available immunotherapies may augment clinical responses.

Published
2021
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7. A Review of the Use of Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy in Pediatric Patients

Author

David J. Byrwa, Clare J. Twist, Joseph Skitzki, Elizabeth Repasky, P. Ben Ham, and Ajay Gupta

Subjects
Cancer Research, Oncology
Abstract

Hyperthermic intraperitoneal chemotherapy (HIPEC) can directly target microscopic peritoneal disease, has achieved regular consideration in the treatment of several adult cancer types, and is more recently being studied in pediatrics. This review paper provides an overview of the use of this modality in pediatrics in order to identify medication choice, discuss post-operative morbidity and mortality, and evaluate impact on overall survival. Four databases were searched including Scopus, PubMed, Embase, and CINAHL and ultimately 37 papers documenting the use of this modality comprising 264 pediatric patients were included. Malignancies treated include desmoplastic small round cell tumor, rhabdomyosarcoma, angiosarcoma, colorectal carcinoma, and mesothelioma, with several rarer tumor types. Cisplatin was the most commonly used drug for HIPEC at varying concentrations for 30–90 min in duration at temperatures of approximately 41–42 °C. Reported toxicities were generally self-limited and there was no post-operative mortality. The impact on overall survival versus systemic chemotherapy and debulking surgery is uncertain due to lack of clinical trials and very small sample size across tumor subsets and the overall pediatric population. The relationship between degree of tumor burden and extent of surgical debulking needs to be further clarified. Future directions include prospective clinical trials, establishment of patient databases to facilitate standardization of HIPEC in pediatric patients, and additional approaches to optimize HIPEC.

Published
2023
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8. Defining the optimal threshold and prognostic utility of pre-treatment hemoglobin level as a biomarker for survival outcomes in head and neck cancer patients receiving chemoradiation

Author

Sung Jun Ma, Han Yu, Michael Khan, Brian Yu, Sharon Santhosh, Udit Chatterjee, Jasmin Gill, Austin Iovoli, Mark Farrugia, Kimberly Wooten, Vishal Gupta, Ryan McSpadden, Moni A Kuriakose, Michael R Markiewicz, Ayham Al-Afif, Wesley L Hicks, Mary E Platek, Mukund Seshadri, Andrew D. Ray, Elizabeth Repasky, and Anurag K. Singh

Subjects
Hemoglobins, Cancer Research, Oncology, Head and Neck Neoplasms, Papillomavirus Infections, Carcinoma, Squamous Cell, Humans, Oral Surgery, Prognosis, Biomarkers, Retrospective Studies
Abstract

We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker.A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes.A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82).Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Published
2022
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9. Abstract 31: Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study

Author

Ashish Gupta, Kristopher Attwood, Kush Gupta, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, and Shipra Gandhi

Subjects
Cancer Research, Oncology
Abstract

Background: Murine tumor models show that cold stress increases tumor growth rate by norepinephrine release, altering the tumor microenvironment (TME). Tumor-bearing mice when housed at standard temperature of 22°Celsius (°C) exhibited a pro-tumorigenic TME (with fewer CD8+ T Cells and an increase in immunosuppressive cells) than mice housed at 30°C. The incidence of cancer has been shown to be higher in colder climates. Achievement of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early stage breast cancer (BC) is associated with improved overall survival (OS) and disease specific survival (DSS). Based on these findings, we hypothesized that pCR would be increased while mortality would be decreased in BC patients (pts) living in warmer climates. Methods: A retrospective, population-based analysis was conducted utilizing the Surveillance, Epidemiology and End Results (SEER) from 1996-2017 and National Cancer Database (NCDB) from 2004-2018, and average annual temperature (AAT) data from the National Centers for Environmental Information. Cut-offs for AAT were obtained using the Youden’s index (for pCR) and maximum log-rank (for OS and DSS) methods. Associations between AAT and both pCR and OS/DSS were evaluated using logistic and Cox regression models, respectively, adjusting for confounders (age, race, education, insurance, BC subtype, treatment). Results: A total of 1,209,332 and 270,496 stage I-III BC pts in the US were analyzed using NCDB and SEER, respectively. In NCDB, 52.1% were hormone receptor (HR)+/HER2-, 8.6% triple negative (TNBC), 7.2% HR+/HER2+ and 3.1% HR-/HER2+ and 29% unknown. 37.7% received chemotherapy, 62.6% radiation and 94.3% surgery. 10.2% pts received NAC and 19.5% (19,021/97,669) achieved pCR. The AAT ranged from 44.7°Fahrenheit (°F) to 62.3°F with median 50.9°F. When adjusting for covariates, pts in regions with AAT > 60.9°F, had a greater chance of achieving pCR compared to AAT < 60.9°F with odds ratio (OR) 1.12 (95% CI 1.07-1.18), p Conclusions: Higher environmental temperatures are associated with significant improvements in rate of pCR, OS and DSS in Stage I-III BC pts. Research focusing on underlying mechanisms and therapeutic strategies to abrogate this disparity is warranted. Citation Format: Ashish Gupta, Kristopher Attwood, Kush Gupta, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, Shipra Gandhi. Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 31.

Published
2022
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10. Adrenergic stress regulates the exhausted phenotype of T cells in the tumor microenvironment

Author

Guanxi Qiao, Minhui Chen, Hemn Mohammadpour, Mark Bucsek, Cameron MacDonald, Bonnie Hylander, and Elizabeth Repasky

Subjects
Immunology, Immunology and Allergy
Abstract

We have shown previously that host adrenergic stress (model of standard ambient temperature-induced chronic stress) slows tumor progression by enhancing CD8+ T-cell activation and limiting the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment (TME). We also found that reducing/blocking β-adrenergic receptor (β-AR) signaling significantly improves anti-tumor immune responses and efficacy of immune checkpoint immunotherapy. It has been reported that expression of immune checkpoint receptors (e.g. PD-1, TIM3, LAG3) is characteristic of exhausted T-cells and has been linked to failure of immune checkpoint inhibitors. Now we report that host adrenergic stress plays a previously unrecognized role in regulating T-cell exhaustion in the TME. In murine melanoma and colon cancer models, we found that propranolol (a pan β-AR blocker) significantly reduces the number of exhausted T-cells expressing immune checkpoint receptors in the TME and increases numbers of T-cells expressing effector cytokines. The overexpression of immune checkpoint receptors has also been associated with mitochondrial dysfunction. Our previous work shows that β-AR signaling during CD8+ T-cell activation in vitro impairs metabolic reprogramming. In new in vivo data, we observed that propranolol treatment increases both glycolysis and oxidative phosphorylation in tumor infiltrating CD8+ T-cells. Together these data suggest that β-AR signaling is a significant factor regulating the functional status of CD8+ T-cells in the TME. Blockade and/or reduction of adrenergic stress has the potential to improve anti-tumor immunity as well as the efficacy of immune checkpoint inhibitors.

Published
2020
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11. 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. 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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
Full Text
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12. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. 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Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. 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Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016
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13. 5th International Symposium on Focused Ultrasound

Author

Menashe Zaaroor, Alon Sinai, Dorit Goldsher, Ayelet Eran, Maria Nassar, Ilana Schlesinger, Jonathon Parker, Vinod Ravikumar, Pejman Ghanouni, Sherman Stein, Casey Halpern, Vibhor Krishna, Amelia Hargrove, Punit Agrawal, Barbara Changizi, Eric Bourekas, Michael Knopp, Ali Rezai, Brian Mead, Namho Kim, Panagiotis Mastorakos, Jung Soo Suk, Wilson Miller, Alexander Klibanov, Justin Hanes, Richard Price, Shutao Wang, Oluyemi Olumolade, Tara Kugelman, Vernice Jackson-Lewis, Maria Eleni Karakatsani, Yang Han, Serge Przedborski, Elisa Konofagou, Kullervo Hynynen, Isabelle Aubert, Gerhard Leinenga, Rebecca Nisbet, Robert Hatch, Anneke Van der Jeugd, Harrison Evans, Jürgen Götz, Ann Van der Jeugd, Paul Fishman, Paul Yarowsky, Victor Frenkel, Shen Wei-Bin, Ben Nguyen, Carlos Sierra Sanchez, Camilo Acosta, Cherry Chen, Shih-Ying Wu, Muna Aryal, Iason T. Papademetriou, Yong-Zhi Zhang, Chanikarn Power, Nathan McDannold, Tyrone Porter, Zsofia Kovacs, Saejeong Kim, Neekita Jikaria, Farhan Qureshi, Michele Bresler, Joseph Frank, Henrik Odéen, George Chiou, John Snell, Nick Todd, Bruno Madore, Dennis Parker, Kim Butts Pauly, Mike Marx, Sumeeth Jonathan, William Grissom, Costas Arvanitis, Gregory Clement, Joshua de Bever, Allison Payne, Douglas Christensen, Guillaume Maimbourg, Mathieu David Santin, Alexandre Houdouin, Stéphane Lehericy, Mickael Tanter, Jean Francois Aubry, Christian Federau, Beat Werner, Dong-Guk Paeng, Zhiyuan Xu, Anders Quigg, Matt Eames, Changzhu Jin, Ashli Everstine, Jason Sheehan, M. Beatriz Lopes, Neal Kassell, James Drake, Karl Price, Lior Lustgarten, Vivian Sin, Charles Mougenot, Elizabeth Donner, Emily Tam, Mojgan Hodaie, Adam Waspe, Thomas Looi, Samuel Pichardo, Wonhye Lee, Yong An Chung, Yujin Jung, In-Uk Song, Seung-Schik Yoo, Hyun-Chul Kim, Jong-Hwan Lee, Charles Caskey, Wolf Zinke, Josh Cosman, Jillian Shuman, Jeffrey Schall, Christian Aurup, Hong Chen, Hermes Kamimura, Antonio Carneiro, Tao Sun, Navid Nazai, Sam Patz, Margaret Livingstone, Todd Mainprize, Yuexi Huang, Ryan Alkins, Martin Chapman, James Perry, Nir Lipsman, Allison Bethune, Arjun Sahgal, Maureen Trudeau, Hao-Li Liu, Po-Hung Hsu, Kuo-Chen Wei, Jonathan Sutton, Phillip Alexander, Eric Miller, Thiele Kobus, Alexandre Carpentier, Michael Canney, Alexandre Vignot, Kevin Beccaria, Delphine Leclercq, Cyril Lafon, Jean Yves Chapelon, Khe Hoang-Xuan, Jean-Yves Delattre, Ahmed Idbaih, David Moore, Alexis Xu, Paul Schmitt, Jessica Foley, Jonathan Sukovich, Charles Cain, Aditya Pandey, Neeraj Chaudhary, Sandra Camelo-Piragua, Steven Allen, Jon Cannata, Dejan Teofilovic, Jim Bertolina, Timothy Hall, Zhen Xu, Julien Grondin, Vincent Ferrera, Gail ter Haar, Petros Mouratidis, Elizabeth Repasky, Kelsie Timbie, Lena Badr, Benjamin Campbell, John McMichael, Andrew Buckner, Jessica Prince, Aaron Stevens, Timothy Bullock, Karin Skalina, Chandan Guha, Franco Orsi, Guido Bonomo, Paolo Della Vigna, Giovanni Mauri, Gianluca Varano, George Schade, Yak-Nam Wang, Venu Pillarisetty, Joo Ha Hwang, Vera Khokhlova, Michael Bailey, Tatiana Khokhlova, Ilya Sinilshchikov, Petr Yuldashev, Yulia Andriyakhina, Wayne Kreider, Adam Maxwell, Oleg Sapozhnikov, Ari Partanen, Jonathan Lundt, Tobias Preusser, Sabrina Haase, Mario Bezzi, Jürgen Jenne, Thomas Langø, Massimo Midiri, Michael Mueller, Giora Sat, Christine Tanner, Stephan Zangos, Matthias Guenther, Andreas Melzer, Arianna Menciassi, Selene Tognarelli, Andrea Cafarelli, Alessandro Diodato, Gastone Ciuti, Sven Rothluebbers, Julia Schwaab, Jan Strehlow, Senay Mihcin, Steffen Tretbar, Thomas Payen, Carmine Palermo, Steve Sastra, Kenneth Olive, Matthew Adams, Vasant Salgaonkar, Serena Scott, Graham Sommer, Chris Diederich, Joan Vidal-Jove, Eloi Perich, Antonio Ruiz, Manuela Velat, David Melodelima, Aurelien Dupre, Jeremy Vincenot, Chen Yao, David Perol, Michel Rivoire, Samantha Tucci, Lisa Mahakian, Brett Fite, Elizabeth Ingham, Sarah Tam, Chang-il Hwang, David Tuveson, Katherine Ferrara, Stephen Scionti, Lili Chen, Dusica Cvetkovic, Xiaoming Chen, Roohi Gupta, Bin Wang, Charlie Ma, Kenneth Bader, Kevin Haworth, Christy Holland, Narendra Sanghvi, Roy Carlson, Wohsing Chen, Christian Chaussy, Stefan Thueroff, Claudio Cesana, Carlo Bellorofonte, Qingguo Wang, Han Wang, Shengping Wang, Junhai Zhang, Alberto Bazzocchi, Alessandro Napoli, Robert Staruch, Chenchen Bing, Sumbul Shaikh, Joris Nofiele, Debra Szczepanski, Michelle Wodzak Staruch, Noelle Williams, Theodore Laetsch, Rajiv Chopra, Jarrett Rosenberg, Rachelle Bitton, Suzanne LeBlang, Joshua Meyer, Mark Hurwitz, Pavel Yarmolenko, Haydar Celik, Avinash Eranki, Viktoriya Beskin, Domiciano Santos, Janish Patel, Matthew Oetgen, AeRang Kim, Peter Kim, Karun Sharma, Alexander Chisholm, Dionne Aleman, Roberto Scipione, Michael Temple, Joao Guilherme Amaral, Ruby Endre, Maria Lamberti-Pasculli, Joost de Ruiter, Fiona Campbell, Jennifer Stimec, Samit Gupta, Manoj Singh, Sevan Hopyan, Gregory Czarnota, David Brenin, Carrie Rochman, Roussanka Kovatcheva, Jordan Vlahov, Katja Zaletel, Julian Stoinov, Matthew Bucknor, Viola Rieke, Jenny Shim, Korgun Koral, Brian Lang, Carlos Wong, Heather Lam, Alexander Shinkov, Jim Hu, Xi Zhang, Jonathan Macoskey, Kimberly Ives, Gabe Owens, Hitinder Gurm, Jiaqi Shi, Matthew Pizzuto, Christopher Dillon, Ivy Christofferson, Elaine Hilas, Jill Shea, Paul Greillier, Bénédicte Ankou, Francis Bessière, Ali Zorgani, Mathieu Pioche, Wojciech Kwiecinski, Julie Magat, Sandrine Melot-Dusseau, Romain Lacoste, Bruno Quesson, Mathieu Pernot, Stefan Catheline, Philippe Chevalier, Fabrice Marquet, Pierre Bour, Fanny Vaillant, Sana Amraoui, Rémi Dubois, Philippe Ritter, Michel Haïssaguerre, Mélèze Hocini, Olivier Bernus, Pamela Tebebi, Scott Burks, Blerta Milo, Michael Gertner, Jimin Zhang, Andrew Wong, Yu Liu, Azadeh Kheirolomoom, Jai Seo, Katherine Watson, Hua Zhang, Josquin Foiret, Alexander Borowsky, Doudou Xu, Maya Thanou, Miguell Centelles, Mike Wright, Maral Amrahli, Po-Wah So, Wladyslaw Gedroyc, Esther Kneepkens, Edwin Heijman, Jochen Keupp, Steffen Weiss, Klaas Nicolay, Holger Grüll, Matthew Nagle, Anastasia V. Nikolaeva, Marina E. Terzi, Sergey A. Tsysar, Bryan Cunitz, Pierre Mourad, Matthew Downs, Georgiana Yang, Qi Wang, Johnny Chen, Justin Farry, Adam Dixon, Zhongmin Du, Ali Dhanaliwala, John Hossack, Ashish Ranjan, Danny Maples, Rachel Wardlow, Jerry Malayer, Akhilesh Ramachandran, Hirofumi Namba, Motohiro Kawasaki, Masashi Izumi, Katsuhito Kiyasu, Ryuichi Takemasa, Masahiko Ikeuchi, Takahiro Ushida, Calum Crake, Satya V. V. N. Kothapalli, Wan Leighton, Zhaorui Wang, H. Michael Gach, William Straube, Michael Altman, Young-sun Kim, Hyo Keun Lim, Hyunchul Rhim, Johanna van Breugel, Manon Braat, Chrit Moonen, Maurice van den Bosch, Mario Ries, Cristina Marrocchio, Susan Dababou, Jae Young Lee, Hyun Hoon Chung, Soo Yeon Kang, Kook Jin Kang, Keon Ho Son, Dandan Zhang, Juan Plata, Peter Jones, Aurea Pascal-Tenorio, Donna Bouley, Aaron Bond, Robert Dallapiazza, Diane Huss, Amy Warren, Scott Sperling, Ryder Gwinn, Binit Shah, W. Jeff Elias, Colleen Curley, Ying Zhang, Karina Negron, Roger Abounader, Gesthimani Samiotaki, Tsang-Wei Tu, Georgios Papadakis, Dima Hammoud, Matthew Silvestrini, Frank Wolfram, Daniel Güllmar, Juergen Reichenbach, Denis Hofmann, Joachim Böttcher, Harald Schubert, Thomas G. Lesser, Scott Almquist, Francisco Camarena, Sergio Jiménez-Gambín, Noé Jiménez, Jin Woo Chang, Vandiver Chaplin, Rebekah Griesenauer, Michael Miga, Nicholas Ellens, Raag Airan, Alfredo Quinones-Hinojosa, Keyvan Farahani, Xue Feng, Samuel Fielden, Li Zhao, Max Wintermark, Craig Meyer, Sijia Guo, Xin Lu, Jiachen Zhuo, Su Xu, Rao Gullapalli, Dheeraj Gandhi, Omer Brokman, Hongchae Baek, Hyungmin Kim, Steven Leung, Taylor Webb, Natalia Vykhodtseva, Thai-Son Nguyen, Chang Kyu Park, Sang Man Park, Na Young Jung, Min Soo Kim, Won Seok Chang, Hyun Ho Jung, Michael Plaksin, Yoni Weissler, Shy Shoham, Eitan Kimmel, Pavel B. Rosnitskiy, Steve Krupa, Eilon Hazan, Omer Naor, Yoav Levy, Noam Maimon, Inbar Brosh, Itamar Kahn, Jessica Cahill, Elodie Constanciel Colas, Adrian Wydra, Roman Maev, Amirah Aly, Ozge Sesenoglu-Laird, Linas Padegimas, Mark Cooper, Barbara Waszczak, Seruz Tehrani, Craig Slingluff, James Larner, Kumari Andarawewa, Eugene Ozhinsky, Rutwik Shah, Roland Krug, Roel Deckers, Sabine Linn, Britt Suelmann, Arjen Witkamp, Paul Vaessen, Paul van Diest, Lambertus W. Bartels, Clemens Bos, Nicolas Borys, Gert Storm, Elsken Van der Wall, Navid Farr, Moez Alnazeer, Prateek Katti, Bradford Wood, Alexis Farrer, Cyril Ferrer, Baudouin Denis de Senneville, Marijn van Stralen, Jingfei Liu, J. Kent Leach, Stephan Zidowitz, Hsin-Lun Lee, Fang-Chi Hsu, Chia-Chun Kuo, Shiu-Chen Jeng, Tung-Ho Chen, Nai-Yi Yang, Jeng-Fong Chiou, Yi-tzu Kao, Chia-Hsin Pan, Jing-Fu Wu, Yi-Chieh Tsai, Sara Johnson, Dawei Li, Ye He, Ioannis Karakitsios, Michael Schwenke, Daniel Demedts, Xu Xiao, Ian Cavin, Emilee Minalga, Robb Merrill, Rock Hadley, Pascal Ramaekers, Martijn de Greef, Kian Shahriari, Mohammad Hossein Parvizi, Kiana Asadnia, Marzieh Chamanara, Seyed Kamran Kamrava, Hamid Reza Chabok, Ruben Stein, Sébastien Muller, Jeremy Tan, Cornel Zachiu, Hans-Peter Erasmus, Glen Van Arsdell, Lee Benson, Kee W. Jang, Mary Angstadt, Bobbi Lewis, Hailey McLean, Martijn Hoogenboom, Dylan Eikelenboom, Martijn den Brok, Pieter Wesseling, Arend Heerschap, Jurgen Fütterer, Gosse Adema, Kevin Wang, Pei Zhong, Joyce Joy, Helen McLeod, Harry Kim, Matthew Lewis, Arda Ozilgen, Peter Zahos, Dezba Coughlin, Xinyan Tang, Jeff Lotz, Kathleen Jedruszczuk, Amitabh Gulati, Stephen Solomon, Elena Kaye, John Mugler, Gaetano Barbato, Gian Luca Scoarughi, Cristiano Corso, Alessandro Gorgone, Ilaria Giuseppina Migliore, Zachary Larrabee, Arik Hananel, Jean-Francois Aubry, Ayele Negussie, Emmanuel Wilson, Reza Seifabadi, Hyungwon Moon, Jeeun Kang, Changbeom Sim, Jin Ho Chang, Hyuncheol Kim, Hak Jong Lee, Noboru Sasaki, Mitsuyoshi Takiguchi, Lukas Sebeke, Xi Luo, Bram de Jager, Maurice Heemels, Christopher Abraham, Laura Curiel, Rémi Berriet, Margit Janát-Amsbury, Joseph Corea, Patrick Peiyong Ye, Ana Clauda Arias, Micheal Lustig, and Bryant Svedin

Subjects
Pathology, medicine.medical_specialty, business.industry, Blood–brain barrier, Focused ultrasound, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Disease therapy, 0302 clinical medicine, medicine.anatomical_structure, medicine, Radiology, Nuclear Medicine and imaging, business, 030217 neurology & neurosurgery
Published
2016
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14. Chronic cold-stress suppresses chemokine production and CD8+ T cell infiltration in the tumor microenvironment (TUM7P.1024)

Author

Matthew Alexander, Kathleen Kokolus, Amanda Costa, Eleanor Clancy-Thompson, Elizabeth Repasky, and David Mullins

Subjects
Immunology, Immunology and Allergy
Abstract

Recently it was reported that maintenance of mice at thermoneutral temperatures (TT, the temperature at which basal metabolism is sufficient to maintain body temperature, 30oC) enhanced antitumor immune responses and reduced tumor growth, relative to standard vivarium temperatures (ST, 22oC). We hypothesized that mice maintained at ST may have impaired production of T cell chemoattractant cytokines and subsequent T cell infiltration. In mice bearing breast tumors or solid or metastatic-like melanomas, intratumoral expression of CXCL9 and CXCL10 (CXCR3-cognate chemokines) was enhanced by maintenance of hosts in TT conditions. Further, tumors of TT-housed mice contained increased numbers of CD8+ T cells. We further hypothesized that the effect of temperature on T cell chemokine pathways may be a result of chronic cold stress, which may induce norepinephrine (NE) production and subsequent activation of β-adrenergic signaling pathways. We observed that pharmacologic blockade of β-adrenergic receptors in mice bearing solid or metastatic-like melanomas recapitulated the increased intratumoral expression of CXCL9 and CXCL10 and increased CD8+ T cell numbers. Because melanoma cells express β-adrenergic receptors, we suggest that chronic cold stress may induce systemic NE production, leading to tumor local activation of receptors and inhibition of tumor-derived chemokine production. These studies suggest potential interventions to improve existing T cell-based immunotherapies.

Published
2015
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15. Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model

Author

Francisco J, Hernandez-Ilizaliturri, Venkata, Jupudy, Julie, Ostberg, Ezogelin, Oflazoglu, Amy, Huberman, Elizabeth, Repasky, and Myron S, Czuczman

Subjects
Neutrophils, Lymphoma, Non-Hodgkin, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Antineoplastic Agents, Complement System Proteins, Mice, SCID, Antigens, CD20, Rats, Killer Cells, Natural, Survival Rate, Antibodies, Monoclonal, Murine-Derived, Mice, Tumor Cells, Cultured, Animals, Humans, Rituximab
Abstract

Rituximab is a chimeric antibody (Ab) directed against the cluster designated (CD) 20 antigen found on normal and malignant B cells. Rituximab activity has been associated with complement-mediated cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Recent studies performed in severe combined immunodeficiency (SCID) mouse models suggest that in vivo rituximab-associated ADCC is mediated via the FcgammaRIII receptor on effector cells. Despite low level expression of FcgammaRIII, neutrophils are also known to induce ADCC primarily via FcgammaRI receptor (CD64). The purpose of this work was to study the effect(s) of neutrophils on the in vivo antitumor activity of rituximab.To better characterize the biological activity of rituximab, we used a human non-Hodgkin's lymphoma animal model by injecting Raji cells i.v. into natural killer (NK) cell-depleted SCID mice. Disseminated disease involving liver, lung, and central nervous system developed, with subsequent death occurring approximately 3 weeks after tumor inoculation. Specifically, 6-8-week-old NK cell-depleted SCID mice were inoculated by tail vein injection with 1 x 10(6) Raji cells on day 0. The animals then were divided into three cohorts: (a) group A received placebo (PBS); (b) group B received rituximab administered via tail vein injection at 10 mg/kg on days 3, 5, 7, and 11; and (c) group C consisted of neutrophil-depleted SCID mice treated with rituximab at 10 mg/kg on the same schedule. Neutrophils were depleted by i.p. administration of 80 microg of rat antimouse Ly-6G (Gr-1) Ab (BD PharMingen, Inc.) on days -1, 4, 9, and 14. The end point of the study was survival. Differences in outcome between treatment groups were analyzed by Kaplan-Meier methodology.Neutrophil- and NK cell-depleted SCID mice (group C) did not respond to rituximab, and the mean survival time was not significantly different from that of control mice. NK cell-depleted SCID mice with intact neutrophil function (group B) responded to rituximab, and 66% remained alive and appeared healthy after a mean follow-up period of 246 days. Overall, NK cell-depleted SCID mice with intact neutrophil function treated with rituximab had statistically longer mean survival as compared with mice in neutrophil-depleted and control groups (161 days versus 28 days versus 22 days, P=0.003).In the absence of neutrophils, rituximab was less effective in controlling lymphoma cell growth or prolonging survival in our B-cell lymphoma SCID mouse model. Neutrophil-induced ADCC appears to contribute to the in vivo antitumor activity of rituximab. Strategies that improve the function of neutrophils, such as granulocyte-macrophage colony-stimulating factor or G-CSF priming, may increase the antitumor effects of rituximab. Additional in vivo animal studies are warranted.

Published
2003

16. Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100

Author

Xiang-Yang, Wang, Xing, Chen, Masoud H, Manjili, Elizabeth, Repasky, Robert, Henderson, and John R, Subjeck

Subjects
CD4-Positive T-Lymphocytes, Vaccines, Synthetic, Membrane Glycoproteins, Melanoma, Experimental, Immunotherapy, Active, CD8-Positive T-Lymphocytes, Cancer Vaccines, Neoplasm Proteins, Mice, Inbred C57BL, Interferon-gamma, Mice, Animals, Female, HSP70 Heat-Shock Proteins, HSP110 Heat-Shock Proteins, Cell Division, Molecular Chaperones, T-Lymphocytes, Cytotoxic, gp100 Melanoma Antigen
Abstract

This report defines a novel approach to heat shock protein vaccine formulation that takes advantage of the chaperoning property of heat shock protein hsp110 to efficiently bind a large protein substrate (specifically, human melanoma-associated antigen gp100) during heat shock. We demonstrate that hsp110 can form chaperone complexes with gp100 and prevent heat-induced aggregation of gp100. The resultant natural hsp110-gp100 complexes are strongly immunogenic as determined by their ability to elicit an antigen-specific IFN-gamma production and a cytotoxic T-cell response. Immunization with the hsp110-gp100 complex protected mice against subsequent challenge with human gp100-transduced B16 melanoma, which involves both CD4(+) and CD8(+) T-cell populations. Administration of the hsp110-gp100 vaccine also significantly suppressed the growth of established tumors in a therapeutic model. Furthermore, the hsp110-gp100 chaperone complex exhibited inhibitory effects on the progression of wild-type B16 tumor, suggesting that the induced immune response by human gp100 cross-reacts with mouse gp100. More importantly, the antitumor response obtained with the hsp110-gp100 complex is more potent than that obtained using Complete Freund's Adjuvant with gp100, whereas no response was observed against mouse hsp110 itself. Thus, the use of hsp110 to form natural chaperone complexes with tumor protein antigens such as gp100 represents a powerful approach to therapeutic vaccine formulation with significant potential for clinical application.

Published
2003

17. Development of a recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of HSP110

Author

Masoud H, Manjili, Robert, Henderson, Xiang-Yang, Wang, Xing, Chen, Ying, Li, Elizabeth, Repasky, Latif, Kazim, and John R, Subjeck

Subjects
CD4-Positive T-Lymphocytes, Vaccines, Synthetic, Receptor, ErbB-2, Mice, SCID, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, Inbred C57BL, Epitopes, Interferon-gamma, Mice, Immunoglobulin G, Animals, Female, HSP70 Heat-Shock Proteins, HSP110 Heat-Shock Proteins
Abstract

Several studies have shown that when purified from a tumor, certain heat shock proteins (HSPs) can function as effective vaccines against the same tumor by virtue of their ability to bind tumor-specific peptides. However, only a small fraction of the associated peptides would be expected to be immunogenic, in addition to which, the clinical application of this vaccine requires the availability of a surgical specimen of sufficient quantity for purification of the HSP. The present study describes a new approach for the development of natural HSP vaccines that do not have these limitations. This approach uses a recombinant HSP that is noncovalently bound to a recombinant tumor protein antigen by heat shock. HSP110 has been selected for this purpose, because it has been shown to be a highly efficient molecular chaperone in binding to large protein substrates. We show that a "natural chaperone complex" between HSP110 and the intracellular domain (ICD) of human epidermal growth factor receptor 2 protein (HER-2)/neu is formed by heat shock. This HSP110-ICD vaccine elicited both CD8(+) and CD4(+) T-cell responses against ICD as determined by an antigen-specific IFN-gamma production in an enzyme-linked immunospot assay (ELISPOT). In vivo depletion studies revealed that the CD8(+) T-cell response was independent of CD4(+) T-cell help. The HSP110-ICD complex also significantly enhanced ICD-specific antibody responses relative to that seen with ICD alone. No CD8(+) T cell or antibody response was detected against HSP110. The use of recombinant HSP110 to form natural chaperone complexes with large protein antigens represents a new and powerful approach for the design of protein-targeted cancer vaccines.

Published
2002

18. Mild cold stress resulting from standard housing conditions for laboratory mice influences baseline dendritic cell properties (TUM2P.896)

Author

Kathleen Kokolus, Haley Spangler, Benjamin Povinelli, Matthew Farren, Kelvin Lee, and Elizabeth Repasky

Subjects
Immunology, Immunology and Allergy
Abstract

The ability of dendritic cells (DC) to stimulate and regulate T cells is critical for effective anti-tumor immunity. Therefore, it is important to recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice which are commonly used to model anti-tumor immunity. Recent data shows that CD8+ T cell frequency within the tumor microenvironment and anti-tumor function is dependent upon the ambient temperature used to house laboratory mice. As DC function is crucial for CD8+ T cell activation, we hypothesized that DC function is also dependent upon housing temperature. We observed increased numbers of splenic DCs (CD11c+ ) in tumor-bearing mice at housed at standard temperature (ST; 22°C) vs. mice housed at a thermoneutral temperature (TT; 30°C) which alleviates the mild cold stress experienced at ST. Despite increased frequency, DCs from mice at ST primarily display immature phenotypes (MHC II+CD86- ), likely rendering them tolerogenic and unable to activate T cells. Further, splenocytes from tumor-bearing mice at ST were unable to induce T cell proliferation following tumor inoculation while DCs from mice at TT elicited T cell activation. These findings likely contribute to faster tumor growth observed in mice at ST vs. TT. This data strongly suggests that the housing temperature can affect fundamental properties of DC function which in turn influence the ability of DCs to regulate the anti-tumor immune response.

Published
2014
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19. Mild cold stress resulting from standard housing conditions for laboratory mice masks the severity of graft vs. host disease in mouse models of bone marrow transplantation (TRAN3P.887)

Author

Nicholas Leigh, Kathleen Kokolus, Jingxin Qiu, Philip. McCarthy, Xuefang Cao, and Elizabeth Repasky

Subjects
Immunology, Immunology and Allergy
Abstract

Clinical bone marrow transplants (BMT) yield lethal graft vs. host disease (GVHD) after transplant of un-manipulated bone marrow (BM). This differs from murine GVHD models that typically require addition of spleen or lymph node derived T cells. Recent work has shown that mice housed at mandated sub-thermoneutral ambient temperatures (22°C) are cold stressed, resulting in heat generation activated by the sympathetic nervous system. Since cold stressed mice exhibit weakened immune responses, we hypothesize that baseline GVHD is reduced compared to that seen in mice at thermoneutral temperatures (30°C). We compared GVHD in mice receiving MHC-mismatched un-manipulated BM while housed at 22 vs. 30°C at which cold stress is alleviated. In this BMT model, mice housed at 22°C show no signs of GVHD, however, we found weight loss and lethal GVHD in mice housed at 30°C. The same trend was observed with MHC-matched allogeneic BMT. As housing at 22°C activates the sympathetic nervous system, we blocked its activation by administering propranolol, a commonly prescribed β-blocker. Following BMT, mice at 22°C treated with β-blocker displayed lethal GVHD similar to untreated mice at 30°C. This suggests that T cell responses are dampened by cold stress through a β-adrenergic pathway which is circumvented by thermoneutral housing. This study provides insight into translational discrepancies of clinical and murine BMT and demonstrates lethal GVHD in a mouse model generated by un-manipulated BM.

Published
2014
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20. Tumor growth and anti-tumor immunity depend upon extent of metabolic energy devoted to thermoregulation in laboratory mice (P2099)

Author

Kathleen Kokolus, Maegan Capitano, Chen-Ting Lee, Jason Eng, Bonnie Hylander, Jeremy Waight, Christopher Gordon, Scott Abrams, and Elizabeth Repasky

Subjects
Immunology, Immunology and Allergy
Abstract

Laboratory mice are housed under relatively cool conditions and even though their core temperature remains normal, mice are cold stressed and exhibit significant increases in metabolic heat production. We compared tumor growth in mice housed at a standard ambient temperature (22oC) and at a thermoneutral temperature (30oC) which reduces metabolic effort needed for maintaining core temperature. We found significantly reduced tumor incidence and growth rates in animals housed at thermoneutral vs standard temperature using four different syngeneic tumor models, including a metastasis model. Because this difference was not seen in SCID or NUDE mice or in mice depleted of CD8+ T cells, we suspected that a prominent result of metabolic cold stress is diminished adaptive immunity. Immunohistochemistry and flow cytometry confirmed the presence of more CD8+ T cells (including antigen-specific cells) within the tumor microenvironment and spleens of animals at thermoneutral vs standard temperature. Conversely, animals at standard temperature had significantly increased infiltration of immunosuppressive cell subsets including GR-1+CD11b+ myeloid derived suppressor cells and Foxp3+ cells. These data reveal a fundamental relationship between energy utilized for thermoregulation and CD8+ T cell-dependent immunity and strongly suggest that immunological data collected from tumor bearing mice housed at standard temperature could be significantly biased by chronic cold stress.

Published
2013
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21. Increased body temperature induces lymphocyte lipid raft aggregation (35.34)

Author

Thomas A Mace, Casey Kilpatrick, Evan Zynda, and Elizabeth Repasky

Subjects
Immunology, Immunology and Allergy
Abstract

Previous recent data reveal that mild heating in vitro of CD4+ and CD8+ T cells (purified from murine splenocytes) at 39.5°C induces the aggregation of lipid rafts; approximately 70% of lymphocytes express aggregated lipid rafts compared to only 20% of cells maintained at 37oC as judged by the distribution of the lipid raft marker, fluorescently labeled GM1. Further, we found that the fluidity of the T cell plasma membrane, as measured by fluorescence anisotropy of TMA-DPH, increases when the temperature is raised from 37° to 39.5°C. Based on these in vitro results, we hypothesized that a physiologically relevant increase in body temperature results in an increase in lipid raft aggregation in T cells in situ. We administered whole body hyperthermia (WBH) to raise the temperature of mice to 39.5°C for 6 hours and immediately harvested and fixed cells from spleen and lymph nodes. Utilizing Imagestream flow cytometry, we observed a 3 fold increase in the number of CD8+ T cells with lipid raft aggregates isolated from WBH mice compared to T cells isolated from normothermic control mice. Lymphocytes from spleen and lymph nodes responded similarly to WBH. Overall, these findings may help to understand the role of physiological temperature shifts (e.g., during febrile episodes and inflammation) on costimulation and lymphocyte activation potential. Supported by NIH P01 CA94045 and RO1 CA71599

Published
2009
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