National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India.
Mol Oncol. 2023 Jun;17(6):1041-1059. doi: 10.1002/1878-0261.13443. Epub 2023 May 11.
Induction of immunoproteasome (IP) expression in tumour cells can enhance antigen presentation and immunogenicity. Recently, the overexpression of IP genes has been associated with better prognosis and response to immune checkpoint blockade (ICB) therapies in melanoma. However, the extent of this association in other solid tumours and how that is influenced by tumour cell-intrinsic and cell-extrinsic factors remain unclear. Here, we address this by exploring the gene expression patterns from available bulk and single-cell transcriptomic data of primary tumours. We find that tumours with high-IP expression exhibit cytotoxic immune cell infiltration and upregulation of IFN-γ and TNF-α pathways in tumour cells. However, the association of IP expression with overall survival (TCGA cohort) and response to ICB therapy (non-TCGA cohorts) is tumour-type specific (better in non-small-cell lung, breast, bladder and thymus; and worse in glioma and renal) and is greatly influenced by pro- or antitumourigenic immune cell infiltration patterns. This emphasises the need for considering immune cell infiltration patterns, along with IP expression, as a prognostic biomarker to predict overall survival or response to ICB therapies in solid tumours, besides melanoma.
诱导肿瘤细胞中免疫蛋白酶体（IP）的表达可以增强抗原呈递和免疫原性。最近，在黑色素瘤中，IP 基因的过表达与更好的预后和对免疫检查点阻断（ICB）治疗的反应相关。然而，这种关联在其他实体瘤中的程度以及肿瘤细胞内在和细胞外在因素如何影响这种关联尚不清楚。在这里，我们通过探索原发性肿瘤的可用批量和单细胞转录组数据中的基因表达模式来解决这个问题。我们发现，高 IP 表达的肿瘤表现出细胞毒性免疫细胞浸润，并在肿瘤细胞中上调 IFN-γ 和 TNF-α 途径。然而，IP 表达与总生存期（TCGA 队列）和 ICB 治疗反应（非 TCGA 队列）的相关性是肿瘤类型特异性的（在非小细胞肺癌、乳腺癌、膀胱癌和胸腺癌中更好；在神经胶质瘤和肾癌中更差），并且受到促癌或抗癌免疫细胞浸润模式的极大影响。这强调了需要考虑免疫细胞浸润模式以及 IP 表达作为预测实体瘤（除黑色素瘤外）总生存期或对 ICB 治疗反应的预后生物标志物，除了黑色素瘤之外。
