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Mikael Pittet

Christopher S Garris, Sean P Arlauckas, Rainer H Kohler, Marcel P Trefny, Seth Garren, Cécile Piot, Camilla Engblom, Christina Pfirschke, Marie Siwicki, Jeremy Gungabeesoon, Gordon J Freeman, Sarah E Warren, SuFey Ong, Erica Browning, Christopher G Twitty, Robert H Pierce, Mai H Le, Alain P Algazi, Adil I Daud, Sara I Pai, Alfred Zippelius, Ralph Weissleder, Mikael J Pittet
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells...
December 18, 2018: Immunity
Hye-Yeong Kim, Ran Li, Thomas S C Ng, Gabriel Courties, Christopher Blake Rodell, Mark Prytyskach, Rainer H Kohler, Mikael Pittet, Matthias Nahrendorf, Ralph Weissleder, Miles A Miller
Tumor associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, 64Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors...
December 3, 2018: ACS Nano
Juhyun Oh, Angela Magnuson, Christophe Benoist, Mikael J Pittet, Ralph Weissleder
Cancer incidence increases with age, but paradoxically, cancers have been found to grow more quickly in young mice compared with aged ones. The cause of differential tumor growth has been debated and, over time, attributed to faster tumor cell proliferation, decreased tumor cell apoptosis, and/or increased angiogenesis in young animals. Despite major advances in our understanding of tumor immunity over the past 2 decades, little attention has been paid to comparing immune cell populations in young and aged mice...
November 2, 2018: JCI Insight
Christopher B Rodell, Sean P Arlauckas, Michael F Cuccarese, Christopher S Garris, Ran Li, Maaz S Ahmed, Rainer H Kohler, Mikael J Pittet, Ralph Weissleder
Tumour-associated macrophages (TAMs) are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet macrophages are highly plastic and can also acquire an anti-tumourigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors (TLRs) TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNPs) lead to efficient drug delivery to TAMs in vivo...
2018: Nature Biomedical Engineering
Mikael J Pittet, Christopher S Garris, Sean P Arlauckas, Ralph Weissleder
Intravital microscopic imaging can uncover fundamental aspects of immune cell behavior in real time in both healthy and pathological states. Here, we discuss approaches for single-cell imaging of adaptive and innate immune cells to explore how they migrate, communicate, and mediate regulatory or effector functions in various tissues throughout the body. We further review how intravital single-cell imaging can be used to study drug effects on immune cells.
September 7, 2018: Science Immunology
Ekaterina Safroneeva, Catherine Saner, Jean-Benoît Rossel, Delphine Golay, Valérie Pittet, Sébastien Godat, Stefan Diem, Patrick Aepli, Mikael Sawatzki, Jan Borovicka, Konstantin Burgmann, Pascal Juillerat, Peter Netzer, Alexander Sendensky, Petr Hruz, Marc Girardin, Luc Biedermann, Thomas Greuter, Stephan Vavricka, Pierre Michetti, Christoph Mueller, Alex Straumann, Alain M Schoepfer
Background and Aims: The prospective, observational Swiss Eosinophilic Esophagitis Cohort Study (SEECS) was set up in 2015 with the following goals in mind: (1) to provide up-to-date epidemiologic data; (2) to assess the appropriateness of care; (3) to evaluate the psychosocial impact; and (4) to foster translational research projects. Data capture relies on validated instruments to assess disease activity and focuses on epidemiologic variables and biosamples (esophageal biopsies and blood specimens)...
March 2018: Inflammatory Intestinal Diseases
Mikhail Binnewies, Edward W Roberts, Kelly Kersten, Vincent Chan, Douglas F Fearon, Miriam Merad, Lisa M Coussens, Dmitry I Gabrilovich, Suzanne Ostrand-Rosenberg, Catherine C Hedrick, Robert H Vonderheide, Mikael J Pittet, Rakesh K Jain, Weiping Zou, T Kevin Howcroft, Elisa C Woodhouse, Robert A Weinberg, Matthew F Krummel
The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed...
May 2018: Nature Medicine
Camilla Engblom, Christina Pfirschke, Rapolas Zilionis, Janaina Da Silva Martins, Stijn A Bos, Gabriel Courties, Steffen Rickelt, Nicolas Severe, Ninib Baryawno, Julien Faget, Virginia Savova, David Zemmour, Jaclyn Kline, Marie Siwicki, Christopher Garris, Ferdinando Pucci, Hsin-Wei Liao, Yi-Jang Lin, Andita Newton, Omar K Yaghi, Yoshiko Iwamoto, Benoit Tricot, Gregory R Wojtkiewicz, Matthias Nahrendorf, Virna Cortez-Retamozo, Etienne Meylan, Richard O Hynes, Marie Demay, Allon Klein, Miriam A Bredella, David T Scadden, Ralph Weissleder, Mikael J Pittet
Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients ( n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+ ) osteoblastic cells...
December 1, 2017: Science
Miles A Miller, Eunha Kim, Michael F Cuccarese, Alec L Plotkin, Mark Prytyskach, Rainer H Kohler, Mikael J Pittet, Ralph Weissleder
The receptor tyrosine kinase Mer (MERTK) is a promising drug target in cancer, where it can influence the metastasis-promoting signaling of both tumor cells and immune cells alike; however, no small molecule probes currently exist to selectively image Mer. In this work, we design and synthesize a selective near-infrared fluorescent molecular probe of Mer (MERi-SiR). Confocal microscopy of metastases in mice reveals predominant probe accumulation in Mer-expressing tumor-associated macrophages.
December 19, 2017: Chemical Communications: Chem Comm
Miles A Miller, Ravi Chandra, Michael F Cuccarese, Christina Pfirschke, Camilla Engblom, Shawn Stapleton, Utsarga Adhikary, Rainer H Kohler, James F Mohan, Mikael J Pittet, Ralph Weissleder
Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor-associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells and, thus, TNP delivery...
May 31, 2017: Science Translational Medicine
Sean P Arlauckas, Christopher S Garris, Rainer H Kohler, Maya Kitaoka, Michael F Cuccarese, Katherine S Yang, Miles A Miller, Jonathan C Carlson, Gordon J Freeman, Robert M Anthony, Ralph Weissleder, Mikael J Pittet
Monoclonal antibodies (mAbs) targeting the immune checkpoint anti-programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time points after administration...
May 10, 2017: Science Translational Medicine
Christina Pfirschke, Marie Siwicki, Hsin-Wei Liao, Mikael J Pittet
Successful antitumor immunity is thought to require T cell entry into tumors, though mechanisms regulating this process remain unclear. In this issue of Cancer Cell, Spranger et al. indicate that chemokines produced by intratumoral Batf3 dendritic cells are critical for effector T cell recruitment. The findings have implications for immunotherapy.
May 8, 2017: Cancer Cell
Michael F Cuccarese, J Matthew Dubach, Christina Pfirschke, Camilla Engblom, Christopher Garris, Miles A Miller, Mikael J Pittet, Ralph Weissleder
Involvement of the immune system in tumour progression is at the forefront of cancer research. Analysis of the tumour immune microenvironment has yielded a wealth of information on tumour biology, and alterations in some immune subtypes, such as tumour-associated macrophages (TAM), can be strong prognostic indicators. Here, we use optical tissue clearing and a TAM-targeting injectable fluorescent nanoparticle (NP) to examine three-dimensional TAM composition, tumour-to-tumour heterogeneity, response to colony-stimulating factor 1 receptor (CSF-1R) blockade and nanoparticle-based drug delivery in murine pulmonary carcinoma...
February 8, 2017: Nature Communications
Ferdinando Pucci, Steffen Rickelt, Andita P Newton, Christopher Garris, Ernesto Nunes, Charles Evavold, Christina Pfirschke, Camilla Engblom, Mari Mino-Kenudson, Richard O Hynes, Ralph Weissleder, Mikael J Pittet
Co-option of host components by solid tumors facilitates cancer progression and can occur in both local tumor microenvironments and remote locations. At present, the signals involved in long-distance communication remain insufficiently understood. Here, we identify platelet factor 4 (PF4, CXCL4) as an endocrine factor whose overexpression in tumors correlates with decreased overall patient survival. Furthermore, engineered PF4 over-production in a Kras-driven lung adenocarcinoma genetic mouse model expanded megakaryopoiesis in bone marrow, augmented platelet accumulation in lungs, and accelerated de novo adenocarcinogenesis...
November 8, 2016: Cell Reports
Marie Siwicki, Camilla Engblom, Mikael J Pittet
The connection between obesity-induced insulin resistance and inflammation is established, but targeting inflammatory mediators like TNF-α and IL-1β have had limited success improving insulin sensitivity in patients. Now, Li et al. (2016) indicate that galectin-3 could be a targetable link between inflammation and insulin sensitivity.
November 8, 2016: Cell Metabolism
Camilla Engblom, Christina Pfirschke, Mikael J Pittet
Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival...
July 2016: Nature Reviews. Cancer
Asaf Spiegel, Mary W Brooks, Samin Houshyar, Ferenc Reinhardt, Michele Ardolino, Evelyn Fessler, Michelle B Chen, Jordan A Krall, Jasmine DeCock, Ioannis K Zervantonakis, Alexandre Iannello, Yoshiko Iwamoto, Virna Cortez-Retamozo, Roger D Kamm, Mikael J Pittet, David H Raulet, Robert A Weinberg
UNLABELLED: Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms...
June 2016: Cancer Discovery
Ferdinando Pucci, Christopher Garris, Charles P Lai, Andita Newton, Christina Pfirschke, Camilla Engblom, David Alvarez, Melissa Sprachman, Charles Evavold, Angela Magnuson, Ulrich H von Andrian, Katharina Glatz, Xandra O Breakefield, Thorsten R Mempel, Ralph Weissleder, Mikael J Pittet
Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169(+) macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans...
April 8, 2016: Science
Christina Pfirschke, Camilla Engblom, Steffen Rickelt, Virna Cortez-Retamozo, Christopher Garris, Ferdinando Pucci, Takahiro Yamazaki, Vichnou Poirier-Colame, Andita Newton, Younes Redouane, Yi-Jang Lin, Gregory Wojtkiewicz, Yoshiko Iwamoto, Mari Mino-Kenudson, Tiffany G Huynh, Richard O Hynes, Gordon J Freeman, Guido Kroemer, Laurence Zitvogel, Ralph Weissleder, Mikael J Pittet
Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used...
February 16, 2016: Immunity
Selvi Ramasamy, Borja Saez, Subhankar Mukhopadhyay, Daching Ding, Alwiya M Ahmed, Xi Chen, Ferdinando Pucci, Rae'e Yamin, Jianfeng Wang, Mikael J Pittet, Cassandra M Kelleher, David T Scadden, David A Sweetser
Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1(Δ/Δ)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Δ/Δ) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells...
February 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
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