The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC.

Humans Antigen Presentation Carcinoma, Non-Small-Cell Lung Lung Neoplasms / pathology Precision Medicine Proteasome Endopeptidase Complex / metabolism Tumor Microenvironment

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
05 2023
Historique:
received: 30 05 2022
accepted: 10 04 2023
medline: 29 5 2023
pubmed: 23 5 2023
entrez: 22 5 2023
Statut: ppublish

Résumé

Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor-immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology.

Identifiants

DOI: 10.1038/s43018-023-00557-4 PMID: 37217651
pubmed: 37217651
doi: 10.1038/s43018-023-00557-4
pii: 10.1038/s43018-023-00557-4
doi:

Substances chimiques

Proteasome Endopeptidase Complex EC 3.4.25.1
PSME4 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

629-647

Subventions

Organisme : Medical Research Council
ID : MC_UP_1201/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V033077/1
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Références

Johnson, D. B., Nebhan, C. A., Moslehi, J. J. & Balko, J. M. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat. Rev. Clin. Oncol. 19, 254–267 (2022).
pubmed: 35082367 pmcid: 8790946 doi: 10.1038/s41571-022-00600-w
Rock, K. L., Reits, E. & Neefjes, J. Present yourself! By MHC class I and MHC class II molecules. Trends Immunol. 37, 724–737 (2016).
pubmed: 27614798 pmcid: 5159193 doi: 10.1016/j.it.2016.08.010
Rousseau, A. & Bertolotti, A. Regulation of proteasome assembly and activity in health and disease. Nat. Rev. Mol. Cell Biol. 19, 697–712 (2018).
pubmed: 30065390 doi: 10.1038/s41580-018-0040-z
Salzmann, U. et al. Mutational analysis of subunit iβ2 (MECL-1) demonstrates conservation of cleavage specificity between yeast and mammalian proteasomes. FEBS Lett. 454, 11–15 (1999).
pubmed: 10413086 doi: 10.1016/S0014-5793(99)00768-1
Driscoll, J., Brown, M. G., Finley, D. & Monaco, J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature 365, 262–264 (1993).
pubmed: 8371781 doi: 10.1038/365262a0
Gaczynska, M., Rock, K. L. & Goldberg, A. L. γ-Interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365, 264–267 (1993).
pubmed: 8396732 doi: 10.1038/365264a0
Winter, M. B. et al. Immunoproteasome functions explained by divergence in cleavage specificity and regulation. eLife 6, e27364 (2017).
pubmed: 29182146 pmcid: 5705213 doi: 10.7554/eLife.27364
Chong, C. et al. High-throughput and sensitive immunopeptidomics platform reveals profound interferonγ-mediated remodeling of the human leukocyte antigen (HLA) ligandome. Mol. Cell. Proteomics 17, 533–548 (2018).
pubmed: 29242379 doi: 10.1074/mcp.TIR117.000383
Javitt, A. et al. Pro-inflammatory cytokines alter the immunopeptidome landscape by modulation of HLA-B expression. Front. Immunol. 10, 141 (2019).
pubmed: 30833945 pmcid: 6387973 doi: 10.3389/fimmu.2019.00141
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e16 (2017).
pubmed: 29033130 pmcid: 5685550 doi: 10.1016/j.cell.2017.09.028
Tripathi, S. C. et al. Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc. Natl Acad. Sci. USA 113, E1555–E1564 (2016).
pubmed: 26929325 pmcid: 4801290 doi: 10.1073/pnas.1521812113
Kalaora, S. et al. Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma. Nat. Commun. 11, 896 (2020).
pubmed: 32060274 pmcid: 7021791 doi: 10.1038/s41467-020-14639-9
Blickwedehl, J. et al. The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. Mol. Cancer Res. 10, 937–944 (2012).
pubmed: 22550082 pmcid: 5261820 doi: 10.1158/1541-7786.MCR-11-0493-T
Ustrell, V., Hoffman, L., Pratt, G. & Rechsteiner, M. Pa200, a nuclear proteasome activator involved in DNA repair. EMBO J. 21, 3516–3525 (2002).
pubmed: 12093752 pmcid: 126083 doi: 10.1093/emboj/cdf333
Welk, V. et al. Inhibition of proteasome activity induces formation of alternative proteasome complexes. J. Biol. Chem. 291, 13147–13159 (2016).
pubmed: 27129254 pmcid: 4933230 doi: 10.1074/jbc.M116.717652
Qian, M.-X. et al. Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell 153, 1012–1024 (2013).
pubmed: 23706739 pmcid: 3983474 doi: 10.1016/j.cell.2013.04.032
Fabre, B. et al. Label-free quantitative proteomics reveals the dynamics of proteasome complexes composition and stoichiometry in a wide range of human cell lines. J. Proteome Res. 13, 3027–3037 (2014).
pubmed: 24804812 doi: 10.1021/pr500193k
Toste Rêgo, A. & da Fonseca, P. C. A. Characterization of fully recombinant human 20S and 20S-PA200 proteasome complexes. Mol. Cell 76, 138–147.e5 (2019).
pubmed: 31473102 pmcid: 6863390 doi: 10.1016/j.molcel.2019.07.014
Tsvetkov, P. et al. Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. Proc. Natl Acad. Sci. USA 114, 382–387 (2017).
pubmed: 28028240 doi: 10.1073/pnas.1619067114
Tanahashi, N. et al. Molecular properties of the proteasome activator PA28 family proteins and γ-interferon regulation. Genes Cells 2, 195–211 (1997).
pubmed: 9189757 doi: 10.1046/j.1365-2443.1997.d01-308.x
Sánchez-Martín, D. et al. Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies. Proc. Natl Acad. Sci. USA 110, 13791–13796 (2013).
pubmed: 23918357 pmcid: 3752212 doi: 10.1073/pnas.1300013110
Kisselev, A. F. F., Akopian, T. N. N., Woo, K. M. M. & Goldberg, A. L. L. The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. J. Biol. Chem. 274, 3363–3371 (1999).
pubmed: 9920878 doi: 10.1074/jbc.274.6.3363
Ruschak, A. M. & Kay, L. E. Proteasome allostery as a population shift between interchanging conformers. Proc. Natl Acad. Sci. USA 109, E3454–E3462 (2012).
pubmed: 23150576 pmcid: 3528551 doi: 10.1073/pnas.1213640109
Yamano, T. et al. Allele-selective effect of PA28 in MHC class I antigen processing. J. Immunol. 181, 1655–1664 (2008).
pubmed: 18641301 doi: 10.4049/jimmunol.181.3.1655
de Graaf, N. et al. PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I-binding peptides in vivo. Eur. J. Immunol. 41, 926–935 (2011).
pubmed: 21360704 pmcid: 3100532 doi: 10.1002/eji.201041040
Murata, S., Takahama, Y., Kasahara, M. & Tanaka, K. The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat. Immunol. 19, 923–931 (2018).
pubmed: 30104634 doi: 10.1038/s41590-018-0186-z
Dick, T. P. et al. Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands. Cell 86, 253–262 (1996).
pubmed: 8706130 doi: 10.1016/S0092-8674(00)80097-5
Wolf-Levy, H. et al. Revealing the cellular degradome by mass spectrometry analysis of proteasome-cleaved peptides. Nat. Biotechnol. 36, 1110–1116 (2018).
doi: 10.1038/nbt.4279
Javitt, A. & Merbl, Y. Global views of proteasome-mediated degradation by mass spectrometry. Expert Rev. Proteomics https://doi.org/10.1080/14789450.2019.1651979 (2019).
Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).
pubmed: 33508232 pmcid: 7933824 doi: 10.1016/j.cell.2021.01.002
Kim, J. Y., Choi, J. K. & Jung, H. Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer. Clin. Epigenetics 12, 1–10 (2020).
doi: 10.1186/s13148-020-00907-4
Gillette, M. A. et al. Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell 182, 200–225.e35 (2020).
pubmed: 32649874 pmcid: 7373300 doi: 10.1016/j.cell.2020.06.013
Kahana, C. & Reiss, Y. Cell-free assay for ubiquitin-independent proteasomal protein degradation. Methods Mol. Biol. 301, 83–96 (2005).
pubmed: 15917628
Pishesha, N., Harmand, T. J. & Ploegh, H. L. A guide to antigen processing and presentation. Nat. Rev. Immunol. 22, 751–764 (2022).
pubmed: 35418563 doi: 10.1038/s41577-022-00707-2
Lavin, Y., Kobayashi, S., Leader, A. & Rahman, A. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–757.e15 (2017).
pubmed: 28475900 pmcid: 5737939 doi: 10.1016/j.cell.2017.04.014
Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).
pubmed: 32269339 pmcid: 7787191 doi: 10.1038/s41586-020-2134-y
Li, S., Wu, J., Zhu, S., Liu, Y. J. & Chen, J. Disease-associated plasmacytoid dendritic cells. Front. Immunol. https://doi.org/10.3389/fimmu.2017.01268 (2017).
Morozov, A. V. & Karpov, V. L. Proteasomes and several aspects of their heterogeneity relevant to cancer. Front. Oncol. 9, 761 (2019).
pubmed: 31456945 pmcid: 6700291 doi: 10.3389/fonc.2019.00761
Cantin, A. M. & Richter, M. V. Cigarette smoke-induced proteostasis imbalance in obstructive lung diseases. Curr. Mol. Med. 12, 836–849 (2012).
pubmed: 22697342 doi: 10.2174/156652412801318746
Kammerl, I. E. et al. Dissecting the molecular effects of cigarette smoke on proteasome function. J. Proteomics 193, 1–9 (2019).
pubmed: 30557664 doi: 10.1016/j.jprot.2018.12.015
Srinivas, U. S., Tan, B. W. Q., Vellayappan, B. A. & Jeyasekharan, A. D. ROS and the DNA damage response in cancer. Redox Biol. https://doi.org/10.1016/j.redox.2018.101084 (2019).
Young, J. H. et al. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer. Bioinformatics 32, 1373–1379 (2016).
pubmed: 26755624 pmcid: 4848405 doi: 10.1093/bioinformatics/btw010
Jiang, T.-X. et al. Proteasome activator PA200 maintains stability of histone marks during transcription and aging. Theranostics 11, 1458 (2021).
pubmed: 33391545 pmcid: 7738882 doi: 10.7150/thno.48744
Wani, P. S., Rowland, M. A., Ondracek, A., Deeds, E. J. & Roelofs, J. Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association. Nat. Commun. 6, 6384 (2015).
pubmed: 25812915 doi: 10.1038/ncomms7384
Marques, A. J., Glanemann, C., Ramos, P. C. & Dohmen, R. J. The C-terminal extension of the β7 subunit and activator complexes stabilize nascent 20 S proteasomes and promote their maturation. J. Biol. Chem. 282, 34869–34876 (2007).
pubmed: 17911101 doi: 10.1074/jbc.M705836200
Boulpicante, M. et al. Tumors escape immunosurveillance by overexpressing the proteasome activator PSME3. Oncoimmunology 9, 1761205 (2020).
pubmed: 32923122 pmcid: 7458623 doi: 10.1080/2162402X.2020.1761205
Sahu, I. & Glickman, M. H. Structural insights into substrate recognition and processing by the 20S proteasome. Biomolecules 11, 1–15 (2021).
doi: 10.3390/biom11020148
Huang, L., Marvin, J. M., Tatsis, N. & Eisenlohr, L. C. Cutting edge: selective role of ubiquitin in MHC class I antigen presentation. J. Immunol. 186, 1904–1908 (2011).
pubmed: 21239720 doi: 10.4049/jimmunol.1003411
Wei, J. et al. Varied role of ubiquitylation in generating MHC class I peptide ligands. J. Immunol. 198, 3835 (2017).
pubmed: 28363906 doi: 10.4049/jimmunol.1602122
Abi Habib, J., Lesenfants, J., Vigneron, N. & Van den Eynde, B. J. Functional differences between proteasome subtypes. Cells 11, 421 (2022).
pubmed: 35159231 pmcid: 8834425 doi: 10.3390/cells11030421
van Endert, P. Intracellular recycling and cross-presentation by MHC class I molecules. Immunol. Rev. 272, 80–96 (2016).
pubmed: 27319344 doi: 10.1111/imr.12424
Buneeva, O. A. & Medvedev, A. E. Ubiquitin-independent degradation of proteins in proteasomes. Biochem. (Mosc.) Suppl. B Biomed. Chem. 12, 203–219 (2018).
Mamrosh, J. L. et al. A systematic interrogation of MHC class I peptide presentation identifies constitutive and compensatory protein degradation pathways. Preprint at bioRxiv https://doi.org/10.1101/2021.10.07.463289 (2022).
Yewdell, J. W., Dersh, D. & Fåhraeus, R. Peptide channeling: the key to MHC class I immunosurveillance? Trends Cell Biol. 29, 929–939 (2019).
pubmed: 31662235 doi: 10.1016/j.tcb.2019.09.004
Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473 (2013).
pubmed: 23298205 pmcid: 4026165 doi: 10.1146/annurev-immunol-032712-095910
Lev, A. et al. Compartmentalized MHC class I antigen processing enhances immunosurveillance by circumventing the law of mass action. Proc. Natl Acad. Sci. USA 107, 6964–6969 (2010).
pubmed: 20351281 pmcid: 2872426 doi: 10.1073/pnas.0910997107
Yewdell, J. W., Norbury, C. C. & Bennink, J. R. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8
pubmed: 10399005 doi: 10.1016/S0065-2776(08)60785-3
Harel, M. et al. Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence. Cell 179, 236–250.e18 (2019).
pubmed: 31495571 pmcid: 7993352 doi: 10.1016/j.cell.2019.08.012
Spits, M. & Neefjes, J. Immunoproteasomes and immunotherapy—a smoking gun for lung cancer? J. Thorac. Dis. 8, E558–E563 (2016).
pubmed: 27501321 pmcid: 4958817 doi: 10.21037/jtd.2016.05.21
Boshuizen, J. & Peeper, D. S. Rational cancer treatment combinations: an urgent clinical need. Mol. Cell 78, 1002–1018 (2020).
pubmed: 32559422 doi: 10.1016/j.molcel.2020.05.031
Pfirschke, C. et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44, 343–354 (2016).
pubmed: 26872698 pmcid: 4758865 doi: 10.1016/j.immuni.2015.11.024
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
pubmed: 29443960 pmcid: 6028240 doi: 10.1038/nature25501
McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).
pubmed: 29867230 pmcid: 6721896 doi: 10.1038/s41591-018-0053-3
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. New Engl. J. Med. 371, 2189–2199 (2014).
pubmed: 25409260 doi: 10.1056/NEJMoa1406498
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
pubmed: 26997480 pmcid: 4808437 doi: 10.1016/j.cell.2016.02.065
Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
pubmed: 26359337 pmcid: 5054517 doi: 10.1126/science.aad0095
Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).
pubmed: 27207943 doi: 10.1093/bioinformatics/btw313
Wickam, H. ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag New York, 2016).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517 pmcid: 1239896 doi: 10.1073/pnas.0506580102
Trujillo, J. A., Sweis, R. F., Bao, R. & Luke, J. J. T cell-inflamed versus non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol. Res. 6, 990–1000 (2018).
pubmed: 30181337 pmcid: 6145135 doi: 10.1158/2326-6066.CIR-18-0277
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
pubmed: 25970248 doi: 10.1038/nature14404
Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 (2017).
pubmed: 28818916 doi: 10.1126/science.aan2507
Thul, P. J. et al. A subcellular map of the human proteome. Science 356, 6340 (2017).
doi: 10.1126/science.aal3321
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 6220 (2015).
doi: 10.1126/science.1260419
Welk, V. et al. Proteasome activator PA200 regulates myofibroblast differentiation. Sci. Rep. 9, 1–11 (2019).
doi: 10.1038/s41598-019-51665-0
Klotz, L. et al. Comprehensive clinical profiling of the Gauting locoregional lung adenocarcinoma donors. Cancer Med. 8, 1486–1499 (2019).
pubmed: 30806043 pmcid: 6488114 doi: 10.1002/cam4.2031
Kohen, R. et al. UTAP: User-friendly Transcriptome Analysis Pipeline. BMC Bioinf. 20, 1–7 (2019).
doi: 10.1186/s12859-019-2728-2
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e21 (2019).
pubmed: 31178118 pmcid: 6687398 doi: 10.1016/j.cell.2019.05.031
Grün, D. et al. Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature 525, 251–255 (2015).
pubmed: 26287467 doi: 10.1038/nature14966
Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).
pubmed: 32269339 pmcid: 7787191 doi: 10.1038/s41586-020-2134-y
Heng, T. S. P. et al. The immunological genome project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
pubmed: 18800157 doi: 10.1038/ni1008-1091
Raudvere, U. et al. G:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453 pmcid: 6602461 doi: 10.1093/nar/gkz369
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281 pmcid: 4302049 doi: 10.1186/s13059-014-0550-8
Vizcaíno, J. A. et al. 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 44, D447–D456 (2016).
pubmed: 26527722 doi: 10.1093/nar/gkv1145

Auteurs

Aaron Javitt (A)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0002-5076-9542

Merav D Shmueli (MD)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. merav.shmueli@weizmann.ac.il.
ORCID: 0000-0002-9196-7633

Matthias P Kramer (MP)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0002-0289-5261

Aleksandra A Kolodziejczyk (AA)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0002-2903-8884

Ivan J Cohen (IJ)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Lihi Radomir (L)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Daoud Sheban (D)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Iris Kamer (I)

Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.

Kevin Litchfield (K)

UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
ORCID: 0000-0002-3725-0914

Elizabeta Bab-Dinitz (E)

Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.

Oranit Zadok (O)

Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.

Vanessa Neiens (V)

Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum Muenchen, Munich, Germany.
Member of the German Center for Lung Research (DZL), Munich, Germany.

Adi Ulman (A)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0002-3175-5006

Hila Wolf-Levy (H)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Avital Eisenberg-Lerner (A)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Assaf Kacen (A)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0003-0709-6132

Michal Alon (M)

Department of Molecular and Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Ana Toste Rêgo (AT)

MRC Laboratory of Molecular Biology, Cambridge, UK.

Elvira Stacher-Priehse (E)

Asklepios Lung Clinic Munich-Gauting, Gauting, Germany.

Michael Lindner (M)

Asklepios Lung Clinic Munich-Gauting, Gauting, Germany.

Ina Koch (I)

Member of the German Center for Lung Research (DZL), Munich, Germany.
Asklepios Lung Clinic Munich-Gauting, Gauting, Germany.
ORCID: 0000-0002-8766-017X

Jair Bar (J)

Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
ORCID: 0000-0002-1224-3646

Charles Swanton (C)

UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
ORCID: 0000-0002-4299-3018

Yardena Samuels (Y)

Member of the German Center for Lung Research (DZL), Munich, Germany.
ORCID: 0000-0002-3349-7266

Yishai Levin (Y)

de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.

Paula C A da Fonseca (PCA)

Department of Molecular and Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
School of Molecular Biosciences, University of Glasgow, Glasgow, UK.

Eran Elinav (E)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
Division of Cancer-Microbiome Research, DKFZ, Heidelberg, Germany.
ORCID: 0000-0002-5775-2110

Nir Friedman (N)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Silke Meiners (S)

Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum Muenchen, Munich, Germany.
Member of the German Center for Lung Research (DZL), Munich, Germany.
Research Center Borstel, Borstel, Germany.
Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany.
ORCID: 0000-0003-3678-7995

Yifat Merbl (Y)

Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. Yifat.merbl@weizmann.ac.il.
ORCID: 0000-0002-3465-2221

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité acquise › Immunité cellulaire › Présentation d'antigène › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Professions de santé › Médecine › Médecine clinique › Médecine de précision › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › The proteasome regulator PSME4 modulates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › The proteasome regulator PSME4 modulates...