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 () and Yardena Samuels ()
Additional contact information
Shelly Kalaora: Weizmann Institute of Science
Joo Sang Lee: National Cancer Institute
Eilon Barnea: Department of Biology, Technion
Ronen Levy: Weizmann Institute of Science
Polina Greenberg: Weizmann Institute of Science
Michal Alon: Weizmann Institute of Science
Gal Yagel: Weizmann Institute of Science
Gitit Bar Eli: Weizmann Institute of Science
Roni Oren: Weizmann Institute of Science
Aviyah Peri: Weizmann Institute of Science
Sushant Patkar: National Cancer Institute
Lital Bitton: Weizmann Institute of Science
Steven A. Rosenberg: National Cancer Institute
Michal Lotem: Hadassah Medical School
Yishai Levin: Weizmann Institute of Science
Arie Admon: Department of Biology, Technion
Eytan Ruppin: National Cancer Institute
Yardena Samuels: Weizmann Institute of Science

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14639-9

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