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

Research output: Contribution to journalArticlepeer-review

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
Pages (from-to)896
Number of pages12
JournalNature Communications
Volume11
Issue number1
Early online date14 Feb 2020
DOIs
StatePublished - 14 Feb 2020

Keywords

  • Antigen Presentation
  • Cysteine Endopeptidases/genetics
  • Humans
  • Immunotherapy
  • Interferon-gamma/genetics
  • Melanoma/diagnosis
  • Prognosis
  • Proteasome Endopeptidase Complex/genetics

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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