Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma

Shelly Kalaora, Joo Sang Lee, Eilon Barnea, Ronen Levy, Polina Greenberg, Michal Alon, Gal Yagel, Gitit Bar Eli, Roni Oren, Aviyah Peri, Sushant Patkar, Lital Bitton, Steven A. Rosenberg, Michal Lotem, Yishai Levin, Arie Admon, Eytan Ruppin, Yardena Samuels*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFNγ) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9, two major components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism underlying this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens diferentially presented after immunoproteasome overexpression. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patientsʼ immune response to checkpoint inhibitors than the tumors’ mutational burden. These results suggest that PSMB8 and PSMB9 expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment.

Original languageEnglish
Article number896
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020
Externally publishedYes

Funding

FundersFunder number
Comisaroff Family Trust
Knell Family and Hamburger Family
Margot and Ernst Hamburger
Meyer Henri Cancer Endowment
Molecular Genetics of Cancer
Rising Tide Foundation
National Cancer InstituteZIABC010763
Melanoma Research Alliance622106
Horizon 2020 Framework Programme754282
H2020 European Research Council712977
European Research CouncilCoG-770854
Israel Science Foundation696/17

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