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Wei Qiu, Ayse B Dincer, Joseph D Janizek, Safiye Celik, Mikael Pittet, Kamila Naxerova, Su-In Lee
Clinically and biologically valuable information may reside untapped in large cancer gene expression data sets. Deep unsupervised learning has the potential to extract this information with unprecedented efficacy but has thus far been hampered by a lack of biological interpretability and robustness. Here, we present DeepProfile, a comprehensive framework that addresses current challenges in applying unsupervised deep learning to gene expression profiles. We use DeepProfile to learn low-dimensional latent spaces for 18 human cancers from 50,211 transcriptomes...
March 17, 2024: bioRxiv
#2
JOURNAL ARTICLE
Anne-Gaëlle Goubet, Mikaël J Pittet
No abstract text is available yet for this article.
March 2024: Nature Immunology
#3
JOURNAL ARTICLE
Noah Enbergs, Elias A Halabi, Anne-Gaëlle Goubet, Kelton Schleyer, Ina R Fredrich, Rainer H Kohler, Christopher S Garris, Mikaël J Pittet, Ralph Weissleder
Tumor-associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9Hi TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM-specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small-molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM-avid systemic nanoformulation is reported...
February 11, 2024: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
#4
JOURNAL ARTICLE
David Barras, Eleonora Ghisoni, Johanna Chiffelle, Angela Orcurto, Julien Dagher, Noémie Fahr, Fabrizio Benedetti, Isaac Crespo, Alizée J Grimm, Matteo Morotti, Stefan Zimmermann, Rafael Duran, Martina Imbimbo, Maria Ochoa de Olza, Blanca Navarro, Krisztian Homicsko, Sara Bobisse, Danny Labes, Zoe Tsourti, Charitini Andriakopoulou, Fernanda Herrera, Rémy Pétremand, Reinhard Dummer, Gregoire Berthod, Anne I Kraemer, Florian Huber, Jonathan Thevenet, Michal Bassani-Sternberg, Niklaus Schaefer, John O Prior, Maurice Matter, Veronica Aedo, Clarisse Dromain, Jesus Corria-Osorio, Stéphanie Tissot, Lana E Kandalaft, Raphael Gottardo, Mikaël Pittet, Christine Sempoux, Olivier Michielin, Urania Dafni, Lionel Trueb, Alexandre Harari, Denarda Dangaj Laniti, George Coukos
Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden...
February 2, 2024: Science Immunology
#5
REVIEW
Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel
In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses...
October 10, 2023: Immunity
#6
JOURNAL ARTICLE
CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
Ruben Bill, Pratyaksha Wirapati, Marius Messemaker, Whijae Roh, Beatrice Zitti, Florent Duval, Máté Kiss, Jong Chul Park, Talia M Saal, Jan Hoelzl, David Tarussio, Fabrizio Benedetti, Stéphanie Tissot, Lana Kandalaft, Marco Varrone, Giovanni Ciriello, Thomas A McKee, Yan Monnier, Maxime Mermod, Emily M Blaum, Irena Gushterova, Anna L K Gonye, Nir Hacohen, Gad Getz, Thorsten R Mempel, Allon M Klein, Ralph Weissleder, William C Faquin, Peter M Sadow, Derrick Lin, Sara I Pai, Moshe Sade-Feldman, Mikael J Pittet
Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized...
August 4, 2023: Science
#7
JOURNAL ARTICLE
Lou Romanens, Prasad Chaskar, Rachel Marcone, Stephan Ryser, Jean-Christophe Tille, Raphael Genolet, Ketty Heimgartner-Hu, Killian Heimgartner, Jonathan S Moore, Nicolas Liaudet, Gürkan Kaya, Mikael J Pittet, Pierre-Yves Dietrich, Mauro Delorenzi, Daniel E Speiser, Alexandre Harari, Petros Tsantoulis, Sana Intidhar Labidi-Galy
The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of tumor microenvironment...
November 1, 2023: International Journal of Cancer. Journal International du Cancer
#8
JOURNAL ARTICLE
Laura Fernandez-Rodriguez, Chiara Cianciaruso, Ruben Bill, Marcel P Trefny, Richard Klar, Nicole Kirchhammer, Mélanie Buchi, Julia Festag, Sven Michel, Rainer H Kohler, Elham Jones, Andre Maaske, Abhishek S Kashyap, Frank Jaschinski, Karen O Dixon, Mikael J Pittet, Alfred Zippelius
BACKGROUND: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy...
May 2023: Journal for Immunotherapy of Cancer
#9
Vincenzo Bronte, Mikael J Pittet
No abstract text is available yet for this article.
May 9, 2023: Immunity
#10
JOURNAL ARTICLE
Jeremy Gungabeesoon, Nicolas A Gort-Freitas, Máté Kiss, Evangelia Bolli, Marius Messemaker, Marie Siwicki, Mehdi Hicham, Ruben Bill, Peter Koch, Chiara Cianciaruso, Florent Duval, Christina Pfirschke, Michael Mazzola, Solange Peters, Krisztian Homicsko, Christopher Garris, Ralph Weissleder, Allon M Klein, Mikael J Pittet
Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy...
March 30, 2023: Cell
#11
JOURNAL ARTICLE
Yves Boucher, Jessica M Posada, Sonu Subudhi, Ashwin S Kumar, Spencer R Rosario, Liqun Gu, Heena Kumra, Mari Mino-Kenudson, Nilesh P Talele, Dan G Duda, Dai Fukumura, Jennifer Y Wo, Jeffrey W Clark, David P Ryan, Carlos Fernandez-Del Castillo, Theodore S Hong, Mikael J Pittet, Rakesh K Jain
PURPOSE: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment. EXPERIMENTAL DESIGN: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy...
April 14, 2023: Clinical Cancer Research
#12
JOURNAL ARTICLE
Chen Wang, Coline Barnoud, Mara Cenerenti, Mengzhu Sun, Irene Caffa, Burak Kizil, Ruben Bill, Yuanlong Liu, Robert Pick, Laure Garnier, Olga A Gkountidi, Louise M Ince, Stephan Holtkamp, Nadine Fournier, Olivier Michielin, Daniel E Speiser, Stéphanie Hugues, Alessio Nencioni, Mikaël J Pittet, Camilla Jandus, Christoph Scheiermann
The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2 . However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume...
February 2023: Nature
#13
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
No abstract text is available yet for this article.
September 13, 2022: Immunity
#14
JOURNAL ARTICLE
Mariia Bilous, Loc Tran, Chiara Cianciaruso, Aurélie Gabriel, Hugo Michel, Santiago J Carmona, Mikael J Pittet, David Gfeller
BACKGROUND: Single-cell RNA sequencing (scRNA-seq) technologies offer unique opportunities for exploring heterogeneous cell populations. However, in-depth single-cell transcriptomic characterization of complex tissues often requires profiling tens to hundreds of thousands of cells. Such large numbers of cells represent an important hurdle for downstream analyses, interpretation and visualization. RESULTS: We develop a framework called SuperCell to merge highly similar cells into metacells and perform standard scRNA-seq data analyses at the metacell level...
August 13, 2022: BMC Bioinformatics
#15
JOURNAL ARTICLE
Jaehee Kim, Juhyun Oh, Hannah M Peterson, Jonathan C T Carlson, Mikael J Pittet, Ralph Weissleder
Treatment with checkpoint inhibitors can be extraordinarily effective in a fraction of patients, particularly those whose tumors are pre-infiltrated by T cells. In others, efficacy is considerably lower, which has led to interest in developing strategies for sensitization to immunotherapy. Using various colorectal cancer mouse models, it is shown that the use of Traf2 and Nck-interacting protein kinase inhibitors (TNIKi) unexpectedly increases tumor infiltration by PD-1+ CD8+ T cells, thus contributing to tumor control...
June 8, 2022: Advanced biology
#16
JOURNAL ARTICLE
Jina Ko, Martin Wilkovitsch, Juhyun Oh, Rainer H Kohler, Evangelia Bolli, Mikael J Pittet, Claudio Vinegoni, David B Sykes, Hannes Mikula, Ralph Weissleder, Jonathan C T Carlson
Cells in complex organisms undergo frequent functional changes, but few methods allow comprehensive longitudinal profiling of living cells. Here we introduce scission-accelerated fluorophore exchange (SAFE), a method for multiplexed temporospatial imaging of living cells with immunofluorescence. SAFE uses a rapid bioorthogonal click chemistry to remove immunofluorescent signals from the surface of labeled cells, cycling the nanomolar-concentration reagents in seconds and enabling multiple rounds of staining of the same samples...
November 2022: Nature Biotechnology
#17
REVIEW
Daniela F Quail, Borko Amulic, Monowar Aziz, Betsy J Barnes, Evgeniy Eruslanov, Zvi G Fridlender, Helen S Goodridge, Zvi Granot, Andrés Hidalgo, Anna Huttenlocher, Mariana J Kaplan, Ilaria Malanchi, Taha Merghoub, Etienne Meylan, Vivek Mittal, Mikael J Pittet, Andrea Rubio-Ponce, Irina A Udalova, Timo K van den Berg, Denisa D Wagner, Ping Wang, Arturo Zychlinsky, Karin E de Visser, Mikala Egeblad, Paul Kubes
Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation...
June 6, 2022: Journal of Experimental Medicine
#18
Mikael J Pittet, Olivier Michielin, Denis Migliorini
No abstract text is available yet for this article.
June 2022: Nature Reviews. Clinical Oncology
#19
REVIEW
Mikael J Pittet, Olivier Michielin, Denis Migliorini
In the past decade, substantial advances have been made in understanding the biology of tumour-associated macrophages (TAMs), and their clinical relevance is emerging. A particular aspect that is becoming increasingly clear is that the interaction of TAMs with cancer cells and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. Therefore, manipulation of TAMs could enable improved disease control in a substantial fraction of patients across a large number of cancer types...
June 2022: Nature Reviews. Clinical Oncology
#20
REVIEW
Marie Siwicki, Mikael J Pittet
Neutrophils have historically been considered a singular, terminally-differentiated cell population, replete with pre-formed granules, poised to react quickly, aggressively, and somewhat non-specifically in the face of a microbial challenge or tissue injury. However, in recent years, neutrophil biologists have started revisiting this simplistic conception. Many studies have identified complexities in neutrophil biology, and these findings have led the field to redefine neutrophil heterogeneity from multiple angles including their development and maturation, their tissue location, and their ability to respond to various (pathological) stimuli...
October 2021: Seminars in Immunology
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