TY - JOUR
T1 - The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC
AU - Javitt, Aaron
AU - Shmueli, Merav D.
AU - Kramer, Matthias P.
AU - Kolodziejczyk, Aleksandra A.
AU - Cohen, Ivan J.
AU - Radomir, Lihi
AU - Sheban, Daoud
AU - Kamer, Iris
AU - Litchfield, Kevin
AU - Bab-Dinitz, Elizabeta
AU - Zadok, Oranit
AU - Neiens, Vanessa
AU - Ulman, Adi
AU - Wolf-Levy, Hila
AU - Eisenberg-Lerner, Avital
AU - Kacen, Assaf
AU - Alon, Michal
AU - Rêgo, Ana Toste
AU - Stacher-Priehse, Elvira
AU - Lindner, Michael
AU - Koch, Ina
AU - Bar, Jair
AU - Swanton, Charles
AU - Samuels, Yardena
AU - Levin, Yishai
AU - da Fonseca, Paula C.A.
AU - Elinav, Eran
AU - Friedman, Nir
AU - Meiners, Silke
AU - Merbl, Yifat
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160095008&partnerID=8YFLogxK
U2 - 10.1038/s43018-023-00557-4
DO - 10.1038/s43018-023-00557-4
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C2 - 37217651
AN - SCOPUS:85160095008
SN - 2662-1347
VL - 4
SP - 629
EP - 647
JO - Nature Cancer
JF - Nature Cancer
IS - 5
ER -
