Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Cancer Data Science Lab, National Cancer Institute, Bethesda, MD, USA.
Nat Commun. 2020 Feb 14;11(1):896. doi: 10.1038/s41467-020-14639-9.
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 patients' 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.
预测黑色素瘤患者免疫治疗的疗效具有挑战性。参与抗原呈递和干扰素 γ（IFNγ）途径的基因改变在肿瘤的免疫反应中起着重要作用。我们在这里描述，免疫蛋白酶体的两个主要成分 PSMB8 和 PSMB9 的过表达可预测黑色素瘤患者的生存更好，并对免疫检查点抑制剂有更好的反应。我们通过使用 HLA 肽组学分析过表达这些亚基的细胞的抗原肽库来研究这种联系的机制。我们发现，过表达免疫蛋白酶体后，患者匹配的肿瘤浸润淋巴细胞对差异呈现的抗原的反应更高。重要的是，我们发现 PSMB8 和 PSMB9 的表达水平是比肿瘤突变负担更能预测黑色素瘤患者对检查点抑制剂免疫反应的重要标志物。这些结果表明，PSMB8 和 PSMB9 的表达水平可以作为黑色素瘤患者免疫检查点治疗分层的重要生物标志物。
