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

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

doi:10.1038/s41467-020-14639-9

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.

Highlights

Predicting the outcome of immunotherapy treatment in melanoma patients is challenging
To identify additional elements that influence the response to immunotherapy, we focused on the immunoproteasome, which is documented to degrade cell proteins to generate peptides for antigen presentation[7]
The majority of high-purity tumors (6/8) exhibiting high immunoproteasome subunit expression and high mutational load (>50th percentile) were from patients who had a durable clinical benefit from the immune-checkpoint therapy (ICT), but notably, here, too, only a few of the patients (3/7) with low immunoproteasome subunit expression and low mutational load (

Summary

Introduction

Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. We find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patientsimmune 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. Abnormalities in antigen presentation and the interferon gamma (IFNγ) pathways, for example, have been shown to affect the response of melanoma patients to immunotherapy[2,3,4,5,6]. A previous study has demonstrated that the immunoproteasome subunits PSMB8 and PSMB9 are overexpressed in melanoma cell lines[13]. We studied their genomic and transcriptomic alteration in melanoma patients analyzing The

Methods

Results

Conclusion