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JOURNAL ARTICLE
Andrea J Radtke, Ekaterina Postovalova, Arina Varlamova, Alexander Bagaev, Maria Sorokina, Olga Kudryashova, Mark Meerson, Margarita Polyakova, Ilia Galkin, Viktor Svekolkin, Sergey Isaev, Daniil Wiebe, Anna Sharun, Alexander Sarachakov, Grigory Perelman, Yaroslav Lozinsky, Ziv Yaniv, Bradley C Lowekamp, Emily Speranza, Li Yao, Stefania Pittaluga, Arthur L Shaffer, Danny Jonigk, James D Phelan, Theresa Davies-Hill, Da Wei Huang, Pavel Ovcharov, Krystle Nomie, Ekaterina Nuzhdina, Nikita Kotlov, Ravshan Ataullakhanov, Nathan Fowler, Michael Kelly, Jagan Muppidi, Jeremy L Davis, Jonathan M Hernandez, Wyndham H Wilson, Elaine S Jaffe, Louis M Staudt, Mark Roschewski, Ronald N Germain
Follicular lymphoma (FL) is a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Dynamic interactions between tumor B cells and the tumor microenvironment (TME) are hypothesized to contribute to the broad spectrum of clinical behaviors observed among FL patients. Despite the urgent need, existing clinical tools do not reliably predict disease behavior...
March 11, 2024: Cancer Cell
#2
Nikki Bialy, Frank Alber, Brenda Andrews, Michael Angelo, Brian Beliveau, Lacramioara Bintu, Alistair Boettiger, Ulrike Boehm, Claire M Brown, Mahmoud Bukar Maina, James J Chambers, Beth A Cimini, Kevin Eliceiri, Rachel Errington, Orestis Faklaris, Nathalie Gaudreault, Ronald N Germain, Wojtek Goscinski, David Grunwald, Michael Halter, Dorit Hanein, John W Hickey, Judith Lacoste, Alex Laude, Emma Lundberg, Jian Ma, Leonel Malacrida, Josh Moore, Glyn Nelson, Elizabeth Kathleen Neumann, Roland Nitschke, Shuichi Onami, Jaime A Pimentel, Anne L Plant, Andrea J Radtke, Bikash Sabata, Denis Schapiro, Johannes Schöneberg, Jeffrey M Spraggins, Damir Sudar, Wouter-Michiel Adrien Maria Vierdag, Niels Volkmann, Carolina Wählby, Siyuan, Wang, Ziv Yaniv, Caterina Strambio-De-Castillia
Together with the molecular knowledge of genes and proteins, biological images promise to significantly enhance the scientific understanding of complex cellular systems and to advance predictive and personalized therapeutic products for human health. For this potential to be realized, quality-assured image data must be shared among labs at a global scale to be compared, pooled, and reanalyzed, thus unleashing untold potential beyond the original purpose for which the data was generated. There are two broad sets of requirements to enable image data sharing in the life sciences...
February 8, 2024: ArXiv
#3
Edward C Schrom, Erin F McCaffrey, Andrea J Radtke, Emily Speranza, Leanne Arakkal, Nishant Thakur, Spencer Grant, Ronald N Germain
Spatial patterns of cells and other entities drive both physiologic and pathologic processes within tissues. While many imaging and transcriptomic methods document tissue organization, discerning these patterns is challenging, especially when they involve multiple entities in complex arrangements. To address this challenge, we present Spatial Patterning Analysis of Cellular Ensembles (SPACE), an R package for analysis of high-plex tissue images generated using any collection modality. Unlike existing platforms, SPACE detects context-dependent associations, quantitative gradients and orientations, and other organizational complexities...
December 10, 2023: bioRxiv
#4
Nadav Yayon, Veronika R Kedlian, Lena Boehme, Chenqu Suo, Brianna Wachter, Rebecca T Beuschel, Oren Amsalem, Krzysztof Polanski, Simon Koplev, Elizabeth Tuck, Emma Dann, Jolien Van Hulle, Shani Perera, Tom Putteman, Alexander V Predeus, Monika Dabrowska, Laura Richardson, Catherine Tudor, Alexandra Y Kreins, Justin Engelbert, Emily Stephenson, Vitalii Kleshchevnikov, Fabrizio De Rita, David Crossland, Marita Bosticardo, Francesca Pala, Elena Prigmore, Nana-Jane Chipampe, Martin Prete, Lijiang Fei, Ken To, Roger A Barker, Xiaoling He, Filip Van Nieuwerburgh, Omer Bayraktar, Minal Patel, Graham E Davies, Muzlifah A Haniffa, Virginie Uhlmann, Luigi D Notarangelo, Ronald N Germain, Andrea J Radtke, John C Marioni, Tom Taghon, Sarah A Teichmann
T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis...
October 27, 2023: bioRxiv
#5
REVIEW
Chen Zhao, Ronald N Germain
Multiplex imaging has emerged as an invaluable tool for immune-oncologists and translational researchers, enabling them to examine intricate interactions among immune cells, stroma, matrix, and malignant cells within the tumor microenvironment (TME). It holds significant promise in the quest to discover improved biomarkers for treatment stratification and identify novel therapeutic targets. Nonetheless, several challenges exist in the realms of study design, experiment optimization, and data analysis. In this review, our aim is to present an overview of the utilization of multiplex imaging in immuno-oncology studies and inform novice researchers about the fundamental principles at each stage of the imaging and analysis process...
October 2023: Journal for Immunotherapy of Cancer
#6
JOURNAL ARTICLE
Waipan Chan, Yuqi M Cao, Xiang Zhao, Edward C Schrom, Dongya Jia, Jian Song, Leah V Sibener, Shen Dong, Ricardo A Fernandes, Clinton J Bradfield, Margery Smelkinson, Juraj Kabat, Jyh Liang Hor, Grégoire Altan-Bonnet, K Christopher Garcia, Ronald N Germain
Checkpoint blockade revolutionized cancer therapy, but we still lack a quantitative, mechanistic understanding of how inhibitory receptors affect diverse signaling pathways. To address this issue, we developed and applied a fluorescent intracellular live multiplex signal transduction activity reporter (FILMSTAR) system to analyze PD-1-induced suppressive effects. These studies identified pathways triggered solely by TCR or requiring both TCR and CD28 inputs. Using presenting cells differing in PD-L1 and CD80 expression while displaying TCR ligands of distinct potency, we found that PD-1-mediated inhibition primarily targets TCR-linked signals in a manner highly sensitive to peptide ligand quality...
December 4, 2023: Journal of Experimental Medicine
#7
JOURNAL ARTICLE
Anna-Maria Globig, Steven Zhao, Jessica Roginsky, Vivien I Maltez, Juan Guiza, Natalia Avina-Ochoa, Maximilian Heeg, Filipe Araujo Hoffmann, Omkar Chaudhary, Jiawei Wang, Gokhan Senturk, Dan Chen, Carolyn O'Connor, Samuel Pfaff, Ronald N Germain, Kurt A Schalper, Brinda Emu, Susan M Kaech
CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1 . Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β1 -adrenergic receptor ADRB1...
September 20, 2023: Nature
#8
REVIEW
Stefan Uderhardt, Georgiana Neag, Ronald N Germain
Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These dynamics often play out deep within tissues, requiring the optical focus to be placed far below the surface of an opaque organ...
September 18, 2023: Annual Review of Pathology
#9
Dimitre R Simeonov, Kyemyung Park, Jessica T Cortez, Arabella Young, Zhongmei Li, Vinh Nguyen, Jennifer Umhoefer, Alyssa C Indart, Jonathan M Woo, Mark S Anderson, John S Tsang, Ronald N Germain, Harikesh S Wong, Alexander Marson
Genetic variants associated with human autoimmune diseases commonly map to non-coding control regions, particularly enhancers that function selectively in immune cells and fine-tune gene expression within a relatively narrow range of values. How such modest, cell-type-selective changes can meaningfully shape organismal disease risk remains unclear. To explore this issue, we experimentally manipulated species-conserved enhancers within the disease-associated IL2RA locus and studied accompanying changes in the progression of autoimmunity...
June 18, 2023: bioRxiv
#10
JOURNAL ARTICLE
Ellen M Quardokus, Diane C Saunders, Elizabeth McDonough, John W Hickey, Christopher Werlein, Christine Surrette, Presha Rajbhandari, Anna Martinez Casals, Hua Tian, Lisa Lowery, Elizabeth K Neumann, Frida Björklund, Taruna V Neelakantan, Josh Croteau, Anne E Wiblin, Jeremy Fisher, April J Livengood, Karen G Dowell, Jonathan C Silverstein, Jeffrey M Spraggins, Gloria S Pryhuber, Gail Deutsch, Fiona Ginty, Garry P Nolan, Simon Melov, Danny Jonigk, Michael A Caldwell, Ioannis S Vlachos, Werner Muller, Nils Gehlenborg, Brent R Stockwell, Emma Lundberg, Michael P Snyder, Ronald N Germain, Jeannie M Camarillo, Neil L Kelleher, Katy Börner, Andrea J Radtke
Multiplexed antibody-based imaging enables the detailed characterization of molecular and cellular organization in tissues. Advances in the field now allow high-parameter data collection (>60 targets); however, considerable expertise and capital are needed to construct the antibody panels employed by these methods. Organ mapping antibody panels are community-validated resources that save time and money, increase reproducibility, accelerate discovery and support the construction of a Human Reference Atlas...
July 19, 2023: Nature Methods
#11
REVIEW
Jyh Liang Hor, Ronald N Germain
Effective adaptive immunity is rendered possible by highly organized tissue architecture and coordinated cellular crosstalk. While detailed spatiotemporal analyses of antigen presentation and adaptive immune activation in secondary lymphoid tissues have been a major focus of study, it is clear that antigen presentation in other tissues also plays a critical role in shaping the immune response. In this article, we concentrate on two opposing aspects of adaptive immunity: tolerance and antitumor immunity, to illustrate how a complex set of antigen presentation mechanisms contributes to maintaining a delicate balance between robust immunity and avoidance of autoimmune pathology...
June 16, 2023: Current Opinion in Immunology
#12
JOURNAL ARTICLE
Frederick R Adler, Alexander R A Anderson, Abhinav Bhushan, Paul Bogdan, Jose Javier Bravo-Cordero, Amy Brock, Yun Chen, Edna Cukierman, Kathleen E DelGiorno, Gerald V Denis, Meghan C Ferrall-Fairbanks, Zev Jordan Gartner, Ronald N Germain, Deborah M Gordon, Ginger Hunter, Mohit Kumar Jolly, Loukia Georgiou Karacosta, Karthikeyan Mythreye, Parag Katira, Rajan P Kulkarni, Matthew L Kutys, Arthur D Lander, Ashley M Laughney, Herbert Levine, Emil Lou, Pedro R Lowenstein, Kristyn S Masters, Dana Pe'er, Shelly R Peyton, Manu O Platt, Jeremy E Purvis, Gerald Quon, Jennifer K Richer, Nicole C Riddle, Analiz Rodriguez, Joshua C Snyder, Gregory Lee Szeto, Claire J Tomlin, Itai Yanai, Ioannis K Zervantonakis, Hannah Dueck
Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.
April 19, 2023: Cell Systems
#13
JOURNAL ARTICLE
Anna Kuchina, Jason Yang, Bree Aldridge, Kevin A Janes, Naeha Subramanian, Nevan J Krogan, Mehdi Bouhaddou, Shirit Einav, Jason Papin, Ronald N Germain
Leading researchers at the intersection of infectious disease and systems biology speak about how systems approaches have influenced modern infectious disease research and what these tools can offer for the future of the field.
December 21, 2022: Cell Systems
#14
JOURNAL ARTICLE
Qin Xu, Pedro Milanez-Almeida, Andrew J Martins, Andrea J Radtke, Kenneth B Hoehn, Cihan Oguz, Jinguo Chen, Can Liu, Juanjie Tang, Gabrielle Grubbs, Sydney Stein, Sabrina Ramelli, Juraj Kabat, Hengameh Behzadpour, Maria Karkanitsa, Jacquelyn Spathies, Heather Kalish, Lela Kardava, Martha Kirby, Foo Cheung, Silvia Preite, Patrick C Duncker, Moses M Kitakule, Nahir Romero, Diego Preciado, Lyuba Gitman, Galina Koroleva, Grace Smith, Arthur Shaffer, Ian T McBain, Peter J McGuire, Stefania Pittaluga, Ronald N Germain, Richard Apps, Daniella M Schwartz, Kaitlyn Sadtler, Susan Moir, Daniel S Chertow, Steven H Kleinstein, Surender Khurana, John S Tsang, Pamela Mudd, Pamela L Schwartzberg, Kalpana Manthiram
Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues...
January 2023: Nature Immunology
#15
JOURNAL ARTICLE
Shah Md Toufiqur Rahman, Mohammad Aqdas, Erik W Martin, Francesco Tomassoni Ardori, Preeyaporn Songkiatisak, Kyu-Seon Oh, Stefan Uderhardt, Sangwon Yun, Quia C Claybourne, Ross A McDevitt, Valentina Greco, Ronald N Germain, Lino Tessarollo, Myong-Hee Sung
In vitro studies suggest that mapping the spatiotemporal complexity of nuclear factor κB (NF-κB) signaling is essential to understanding its function. The lack of tools to directly monitor NF-κB proteins in vivo has hindered such efforts. Here, we introduce reporter mice with the endogenous RelA (p65) or c-Rel labeled with distinct fluorescent proteins and a double knockin with both subunits labeled. Overcoming hurdles in simultaneous live-cell imaging of RelA and c-Rel, we show that quantitative features of signaling reflect the identity of activating ligands, differ between primary and immortalized cells, and shift toward c-Rel in microglia from aged brains...
November 22, 2022: Cell Reports
#16
Anita Gola, Michael G Dorrington, Emily Speranza, Claudia Sala, Rochelle M Shih, Andrea J Radtke, Harikesh S Wong, Antonio P Baptista, Jonathan M Hernandez, Gastone Castellani, Iain D C Fraser, Ronald N Germain
No abstract text is available yet for this article.
October 24, 2022: Nature
#17
JOURNAL ARTICLE
Yinghong Hu, William H Hudson, Haydn T Kissick, Christopher B Medina, Antonio P Baptista, Chaoyu Ma, Wei Liao, Ronald N Germain, Shannon J Turley, Nu Zhang, Rafi Ahmed
Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells...
October 3, 2022: Journal of Experimental Medicine
#18
JOURNAL ARTICLE
Nathan P Manes, Jessica M Calzola, Pauline R Kaplan, Iain D C Fraser, Ronald N Germain, Martin Meier-Schellersheim, Aleksandra Nita-Lazar
The Toll-like receptor (TLR) and chemotaxis pathways are key components of the innate immune system. Subtle variation in the concentration, timing, and molecular structure of the ligands are known to affect downstream signaling and the resulting immune response. Computational modeling and simulation at the molecular interaction level can be used to study complex biological pathways, but such simulations require protein concentration values as model parameters. Here we report the development and application of targeted mass spectrometry assays to measure the absolute abundance of proteins of the mouse macrophage Toll-like receptor 4 (TLR4) and chemotaxis pathways...
August 12, 2022: Scientific Data
#19
JOURNAL ARTICLE
Abigail Wong-Rolle, Qiang Dong, Yunhua Zhu, Prajan Divakar, Jyh Liang Hor, Noemi Kedei, Madeline Wong, Desiree Tillo, Elizabeth A Conner, Arun Rajan, David S Schrump, Chengcheng Jin, Ronald N Germain, Chen Zhao
BACKGROUND: The lung intratumor microbiome influences lung cancer tumorigenesis and treatment responses, but detailed data on the extent, location, and effects of microbes within lung tumors are missing, information needed for improved prognosis and treatment. METHODS: To address this gap, we developed a novel spatial meta-transcriptomic method simultaneously detecting the expression level of 1,811 host genes and 3 microbe targets (bacteria, fungi, and cytomegalovirus)...
July 2022: Journal for Immunotherapy of Cancer
#20
JOURNAL ARTICLE
Xiang Zhao, Elizabeth M Kolawole, Waipan Chan, Yinnian Feng, Xinbo Yang, Marvin H Gee, Kevin M Jude, Leah V Sibener, Polly M Fordyce, Ronald N Germain, Brian D Evavold, K Christopher Garcia
Adoptive cell therapy using engineered T cell receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide-major histocompatibility complexes (pMHCs). Affinity-matured TCRs can enhance the efficacy of TCR-T cell therapy but can also cross-react with off-target antigens, resulting in organ immunopathology. We developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding through the acquisition of catch bonds...
April 8, 2022: Science
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