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Javitt, A.* ; Shmueli, M.D.* ; Kramer, M.P.* ; Kolodziejczyk, A.A.* ; Cohen, I.J.* ; Radomir, L.* ; Sheban, D.* ; Kamer, I.* ; Litchfield, K.* ; Bab-Dinitz, E.* ; Zadok, O.* ; Neiens, V. ; Ulman, A.* ; Wolf-Levy, H.* ; Eisenberg-Lerner, A.* ; Kacen, A.* ; Alon, M.* ; Rêgo, A.T.* ; Stacher-Priehse, E.* ; Lindner, M.* ; Koch, I.* ; Bar, J.* ; Swanton, C.* ; Samuels, Y.* ; Levin, Y.* ; da Fonseca, P.C.A.* ; Elinav, E.* ; Friedman, N.* ; Meiners, S. ; Merbl, Y.*

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

Nat. Cancer 4, 629-647 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Mhc Class-i; 20 S-proteasomes; Enrichment Analysis; Gamma-interferon; Ctla-4 Blockade; Reveals; Cancer; Pa28; Expression; Tumors

ISSN (print) / ISBN 2662-1347

e-ISSN 2662-1347

Journal Nature Cancer

Quellenangaben Volume: 4, Issue: 5, Pages: 629-647

Publisher Springer

Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Lung Biology (LHI)
Lung Health and Immunity (LHI)

Grants European Research Council (ERC)

Marie Sklodowska-Curie Individual Fellowship
Abisch-Frenkel Foundation for the Promotion of Life Sciences
Melanoma Research Alliance award
Cancer Research Institute/Israel Cancer Research Fund CLIP Grant
Israel Science Foundation
I-CORE Program of the Planning and Budgeting Committee
European Union