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

Autor: Javitt A; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Shmueli MD; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. merav.shmueli@weizmann.ac.il., Kramer MP; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Kolodziejczyk AA; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Cohen IJ; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Radomir L; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Sheban D; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Kamer I; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Litchfield K; UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK., Bab-Dinitz E; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Zadok O; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., 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., Ulman A; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Wolf-Levy H; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Eisenberg-Lerner A; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Kacen A; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Alon M; Department of Molecular and Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Rêgo AT; MRC Laboratory of Molecular Biology, Cambridge, UK., Stacher-Priehse E; Asklepios Lung Clinic Munich-Gauting, Gauting, Germany., Lindner M; Asklepios Lung Clinic Munich-Gauting, Gauting, Germany., Koch I; Member of the German Center for Lung Research (DZL), Munich, Germany.; Asklepios Lung Clinic Munich-Gauting, Gauting, Germany., Bar J; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Swanton C; UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK., Samuels Y; Member of the German Center for Lung Research (DZL), Munich, Germany., 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., da Fonseca PCA; Department of Molecular and Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; School of Molecular Biosciences, University of Glasgow, Glasgow, UK., Elinav E; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.; Division of Cancer-Microbiome Research, DKFZ, Heidelberg, Germany., Friedman N; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., 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., Merbl Y; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. Yifat.merbl@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2023 May; Vol. 4 (5), pp. 629-647. Date of Electronic Publication: 2023 May 22.
DOI: 10.1038/s43018-023-00557-4
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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