المؤلفون: Mitamura, Yasutaka, Schulz, Daniel, Oro, Saskia, Li, Nick, Kolm, Isabel, Lang, Claudia, Ziadlou, Reihane, Tan, Ge, Bodenmiller, Bernd, Steiger, Peter, Marzano, Angelo, Prost, Nicolas, Caudin, Olivier, Levesque, Mitchell, Stoffel, Corinne, Schmid‐Grendelmeier, Peter, Maverakis, Emanual, Akdis, Cezmi A, Brüggen, Marie‐Charlotte

المصدر: Allergy. 77(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Biotechnology, Inflammatory and immune system, Good Health and Well Being, CD8-Positive T-Lymphocytes, COVID-19, Exanthema, Humans, Pharmaceutical Preparations, Proteomics, SARS-CoV-2, coronavirus, drug-induced maculopapular exanthema, Immunology, Allergy

الوصف: BackgroundCoronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR.MethodsBlood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19-related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed.ResultsIMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+ T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features.ConclusionA systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8+ T cells in severe COVID-19 patients, which in turn may impact the development of MDR.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7m08r973Test

المؤلفون: Parikh, Roma, Parikh, Shivang, Berzin, Daniella, Vaknine, Hananya, Ovadia, Shai, Likonen, Daniela, Greenberger, Shoshana, Scope, Alon, Elgavish, Sharona, Nevo, Yuval, Plaschkes, Inbar, Nizri, Eran, Kobiler, Oren, Maliah, Avishai, Zaremba, Laureen, Mohan, Vishnu, Sagi, Irit, Ashery-Padan, Ruth, Carmi, Yaron, Luxenburg, Chen, Hoheisel, Jörg D, Khaled, Mehdi, Levesque, Mitchell P, Levy, Carmit

الوصف: Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as “second-hand” EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression.

وصف الملف: application/pdf

العلاقة: The EMBO Journal; https://hdl.handle.net/1721.1/154934Test; Parikh, Roma, Parikh, Shivang, Berzin, Daniella, Vaknine, Hananya, Ovadia, Shai et al. 2024. "Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification." The EMBO Journal.

الإتاحة: https://hdl.handle.net/1721.1/154934Test

المؤلفون: Schlenker, Ramona, Schwalie, Petra C, Dettling, Steffen, Huesser, Tamara, Irmisch, Anja, Mariani, Marisa, Martínez Gómez, Julia M, Ribeiro, Alison, Limani, Florian, Herter, Sylvia, Yángüez, Emilio, Hoves, Sabine, Somandin, Jitka, Siebourg-Polster, Juliane, Kam-Thong, Tony, de Matos, Ines Grazina, Umana, Pablo, Dummer, Reinhard, Levesque, Mitchell P, Bacac, Marina

المصدر: Schlenker, Ramona; Schwalie, Petra C; Dettling, Steffen; Huesser, Tamara; Irmisch, Anja; Mariani, Marisa; Martínez Gómez, Julia M; Ribeiro, Alison; Limani, Florian; Herter, Sylvia; Yángüez, Emilio; Hoves, Sabine; Somandin, Jitka; Siebourg-Polster, Juliane; Kam-Thong, Tony; de Matos, Ines Grazina; Umana, Pablo; Dummer, Reinhard; Levesque, Mitchell P; Bacac, Marina (2024). Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma. Med:Epub ahead of print.

مصطلحات موضوعية: Dermatology Clinic, 610 Medicine & health, General Medicine

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/259128/1/ZORA_pdf.pdfTest; info:pmid/38593812; urn:issn:2666-6340

الإتاحة: https://doi.org/10.5167/uzh-259128Test
https://doi.org/10.1016/j.medj.2024.03.015Test
https://www.zora.uzh.ch/id/eprint/259128Test/
https://www.zora.uzh.ch/id/eprint/259128/1/ZORA_pdf.pdfTest

المؤلفون: Jahromi, Neda Haghayegh, Gkountidi, Anastasia-Olga, Collado-Diaz, Victor, Blatter, Katharina, Bauer, Aline, Zambounis, Lito, Medina Sanchez, Jessica Danielly, id_orcid:0 000-0002-8877-665X, Russo, Erica, Runge, Peter, Restivo, Gaetana, Gousopoulos, Epameinondas, Lindenblatt, Nicole, Levesque, Mitchell P., Halin, Cornelia

المصدر: Cells, 13 (5)

مصطلحات موضوعية: CD112, Nectin-2, Dendritic cells, Lymphatic endothelial cells, Lymphatic migration, Human

الوصف: Dendritic cell (DC) migration from peripheral tissues via afferent lymphatic vessels to draining lymph nodes (dLNs) is important for the organism’s immune regulation and immune protection. Several lymphatic endothelial cell (LEC)-expressed adhesion molecules have thus far been found to support transmigration and movement within the lymphatic vasculature. In this study, we investigated the contribution of CD112, an adhesion molecule that we recently found to be highly expressed in murine LECs, to this process. Performing in vitro assays in the murine system, we found that transmigration of bone marrow-derived dendritic cells (BM-DCs) across or adhesion to murine LEC monolayers was reduced when CD112 was absent on LECs, DCs, or both cell types, suggesting the involvement of homophilic CD112–CD112 interactions. While CD112 was highly expressed in murine dermal LECs, CD112 levels were low in endogenous murine dermal DCs and BM-DCs. This might explain why we observed no defect in the in vivo lymphatic migration of adoptively transferred BM-DCs or endogenous DCs from the skin to dLNs. Compared to murine DCs, human monocyte-derived DCs expressed higher CD112 levels, and their migration across human CD112-expressing LECs was significantly reduced upon CD112 blockade. CD112 expression was also readily detected in endogenous human dermal DCs and LECs by flow cytometry and immunofluorescence. Upon incubating human skin punch biopsies in the presence of CD112-blocking antibodies, DC emigration from the tissue into the culture medium was significantly reduced, indicating impaired lymphatic migration. Overall, our data reveal a contribution of CD112 to human DC migration. ; ISSN:2073-4409

وصف الملف: application/application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/wos/001182773300001; info:eu-repo/grantAgreement/SNF/Projekte Lebenswissenschaften/182528; http://hdl.handle.net/20.500.11850/662635Test

الإتاحة: https://doi.org/20.500.11850/662635Test
https://doi.org/10.3929/ethz-b-000662635Test
https://doi.org/10.3390/cells13050424Test
https://hdl.handle.net/20.500.11850/662635Test

المؤلفون: Goetze, Sandra, id_orcid:0 000-0001-6880-8020, van Drogen, Audrey, Albinus, Jonas B., Fort, Kyle L., Gandhi, Tejas, Robbiani, Damiano, Laforte, Véronique, Reiter, Lukas, Levesque, Mitchell P., Xuan, Yue, Wollscheid, Bernd, id_orcid:0 000-0002-3923-1610

المصدر: Clinical Proteomics, 21 (1)

مصطلحات موضوعية: Diagnostics, Clinical phenotyping, Melanoma, Proteotyping, Hybrid-PRM/DIA, Hybrid-DIA, Data-independent acquisition (DIA), Parallel reaction monitoring (PRM), Translational proteomics, Molecular tumor board

الوصف: Background Clinical samples are irreplaceable, and their transformation into searchable and reusable digital biobanks is critical for conducting statistically empowered retrospective and integrative research studies. Currently, mainly data-independent acquisition strategies are employed to digitize clinical sample cohorts comprehensively. However, the sensitivity of DIA is limited, which is why selected marker candidates are often additionally measured targeted by parallel reaction monitoring.Methods Here, we applied the recently co-developed hybrid-PRM/DIA technology as a new intelligent data acquisition strategy that allows for the comprehensive digitization of rare clinical samples at the proteotype level. Hybrid-PRM/DIA enables enhanced measurement sensitivity for a specific set of analytes of current clinical interest by the intelligent triggering of multiplexed parallel reaction monitoring (MSxPRM) in combination with the discovery-driven digitization of the clinical biospecimen using DIA. Heavy-labeled reference peptides were utilized as triggers for MSxPRM and monitoring of endogenous peptides.Results We first evaluated hybrid-PRM/DIA in a clinical context on a pool of 185 selected proteotypic peptides for tumor-associated antigens derived from 64 annotated human protein groups. We demonstrated improved reproducibility and sensitivity for the detection of endogenous peptides, even at lower concentrations near the detection limit. Up to 179 MSxPRM scans were shown not to affect the overall DIA performance. Next, we applied hybrid-PRM/DIA for the integrated digitization of biobanked melanoma samples using a set of 30 AQUA peptides against 28 biomarker candidates with relevance in molecular tumor board evaluations of melanoma patients. Within the DIA-detected approximately 6500 protein groups, the selected marker candidates such as UFO, CDK4, NF1, and PMEL could be monitored consistently and quantitatively using MSxPRM scans, providing additional confidence for supporting future clinical ...

وصف الملف: application/application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/wos/001197004000001; http://hdl.handle.net/20.500.11850/668274Test

الإتاحة: https://doi.org/20.500.11850/668274Test
https://doi.org/10.3929/ethz-b-000668274Test
https://doi.org/10.1186/s12014-024-09478-5Test
https://hdl.handle.net/20.500.11850/668274Test

المؤلفون: Chang, Yun-Tsan, Prompsy, Pacôme, Kimeswenger, Susanne, Tsai, Yi-Chien, Ignatova, Desislava, Pavlova, Olesya, Iselin, Christoph, French, Lars E., Levesque, Mitchell P., Kuonen, François, Bobrowicz, Malgorzata, Brunner, Patrick M., Pascolo, Steve, Hoetzenecker, Wolfram, Guenova, Emmanuella

المساهمون: Promedica Stiftung, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Université de Lausanne

المصدر: Nature Communications ; volume 15, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32β–major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients’ skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.

الإتاحة: https://doi.org/10.1038/s41467-024-45083-8Test
https://www.nature.com/articles/s41467-024-45083-8.pdfTest
https://www.nature.com/articles/s41467-024-45083-8Test

المؤلفون: Elbatsh, Ahmed M. O., Amin-Mansour, Ali, Haberkorn, Anne, Textor, Claudia, Ebel, Nicolas, Renard, Emilie, Koch, Lisa M., Groenveld, Femke C., Piquet, Michelle, Naumann, Ulrike, Ruddy, David A., Romanet, Vincent, Martínez Gómez, Julia M., Shirley, Matthew D., Wipfli, Peter, Schnell, Christian, Wartmann, Markus, Rausch, Martin, Jager, Martine J., Levesque, Mitchell P., Maira, Sauveur-Michel, Manchado, Eusebio

المصدر: Nature Cancer ; ISSN 2662-1347

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients’ tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

الإتاحة: https://doi.org/10.1038/s43018-023-00710-zTest
https://www.nature.com/articles/s43018-023-00710-z.pdfTest
https://www.nature.com/articles/s43018-023-00710-zTest

المؤلفون: Lattmann, Evelyn Ruth, Raess, Luca, Tognetti, Marco, Gomez, Julia Martinez, Lapaire, Valérie, Bruderer, Roland, Reiter, Lukas, Hiltbrunner, Stefanie, Curioni-Fontecedro, Alessandra, Feng, Yuehan, Steinmetz, Lars M, Levesque, Mitchell P

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0039Test

المؤلفون: Newell, Felicity, Kong, Yan, Wilmott, James S, Johansson, Peter A, Ferguson, Peter M, Cui, Chuanliang, Li, Zhongwu, Kazakoff, Stephen H, Burke, Hazel, Dodds, Tristan J, Patch, Ann-Marie, Nones, Katia, Tembe, Varsha, Shang, Ping, van der Weyden, Louise, Wong, Kim, Holmes, Oliver, Lo, Serigne, Leonard, Conrad, Wood, Scott, Xu, Qinying, Rawson, Robert V, Mukhopadhyay, Pamela, Dummer, Reinhard, Levesque, Mitchell P, Jönsson, Göran, Wang, Xuan, Yeh, Iwei, Wu, Hong, Joseph, Nancy, Bastian, Boris C, Long, Georgina V, Spillane, Andrew J, Shannon, Kerwin F, Thompson, John F, Saw, Robyn PM, Adams, David J, Si, Lu, Pearson, John V, Hayward, Nicholas K, Waddell, Nicola, Mann, Graham J, Guo, Jun, Scolyer, Richard A

المصدر: Nature communications. 10(1)

مصطلحات موضوعية: Melanocytes, Humans, Melanoma, Telomerase, Signal Transduction, Point Mutation, Female, Male, Cyclin-Dependent Kinase 4, Proto-Oncogene Proteins c-mdm2, DNA Copy Number Variations, Biomarkers, Tumor, Whole Genome Sequencing, Biomarkers, Tumor

الوصف: Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/60f6m57rTest

المؤلفون: Li, Yan, Tinoco, Roberto, Elmén, Lisa, Segota, Igor, Xian, Yibo, Fujita, Yu, Sahu, Avinash, Zarecki, Raphy, Marie, Kerrie, Feng, Yongmei, Khateb, Ali, Frederick, Dennie T, Ashkenazi, Shiri K, Kim, Hyungsoo, Perez, Eva Guijarro, Day, Chi-Ping, Segura Muñoz, Rafael S, Schmaltz, Robert, Yooseph, Shibu, Tam, Miguel A, Zhang, Tongwu, Avitan-Hersh, Emily, Tzur, Lihi, Roizman, Shoshana, Boyango, Ilanit, Bar-Sela, Gil, Orian, Amir, Kaufman, Randal J, Bosenberg, Marcus, Goding, Colin R, Baaten, Bas, Levesque, Mitchell P, Dummer, Reinhard, Brown, Kevin, Merlino, Glenn, Ruppin, Eytan, Flaherty, Keith, Ramer-Tait, Amanda, Long, Tao, Peterson, Scott N, Bradley, Linda M, Ronai, Ze'ev A

المصدر: Nature communications. 10(1)

مصطلحات موضوعية: Intestines, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Bacteria, Melanoma, Ubiquitin-Protein Ligases, Antimicrobial Cationic Peptides, Membrane Proteins, Cell Proliferation, Unfolded Protein Response, Gastrointestinal Microbiome, Inbred C57BL, Knockout

الوصف: Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6qt5b0dhTest