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.

中文翻译：

---

免疫蛋白酶体表达与黑色素瘤的更好预后和对检查点疗法的反应有关。

预测黑素瘤患者免疫治疗的结果具有挑战性。涉及抗原呈递和干扰素γ（IFNγ）途径的基因改变在对肿瘤的免疫反应中起重要作用。我们在此描述，免疫蛋白酶体的两个主要组成部分PSMB8和PSMB9的过表达预示着更好的生存率和对黑色素瘤患者免疫检查点抑制剂反应的改善。我们通过分析使用HLA肽组学过表达这些亚基的细胞的抗原肽库来研究这种连接的机制。我们发现患者匹配的肿瘤浸润淋巴细胞对免疫蛋白酶体过表达后差异表达的抗原有更高的反应。重要的，我们发现，PSMB8和PSMB9的表达水平比黑素瘤患者对检查点抑制剂的免疫反应更能预测肿瘤的突变负担。这些结果表明PSMB8和PSMB9的表达水平可以作为重要的生物标志物，用于对黑色素瘤患者进行免疫检查点治疗。