Placke Jan-Malte, Bottek Jenny, Váraljai Renata, Shannan Batool, Scharfenberg Sarah, Krisp Christoph, Spangenberg Philippa, Soun Camille, Siemes Devon, Borgards Lars, Hoffmann Franziska, Zhao Fang, Paschen Anette, Schlueter Hartmut, von Eggeling Ferdinand, Helfrich Iris, Rambow Florian, Ugurel Selma, Tasdogan Alpaslan, Schadendorf Dirk, Engel Daniel R, Roesch Alexander
Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Germany.
Br J Dermatol. 2025 Feb 18;192(3):481-491. doi: 10.1093/bjd/ljae433.
The tumour microenvironment significantly influences the clinical response of patients to therapeutic immune checkpoint inhibition (ICI), but a comprehensive understanding of the underlying immune-regulatory proteome is still lacking.
To decipher targetable biologic processes that determine tumour-infiltrating lymphocytes (TiLs) as a cellular equivalent of clinical response to ICI.
We mapped the spatial distribution of proteins in TiL-enriched vs. TiL-low compartments in melanoma by combining microscopy, matrix-assisted laser desorption mass spectrometry imaging and liquid chromatography-mass spectrometry, as well as computational data mining. Pharmacological modulation of sirtuin 1 (SIRT1) activity in syngeneic mouse models was used to evaluate the efficacy of pharmacological SIRT1 activation in two syngeneic melanoma mouse models, one known to be α-programmed cell death protein 1 (PD-1) sensitive and the other α-PD-1 resistant.
Spatial proteomics and gene ontology-based enrichment analysis identified > 145 proteins enriched in CD8high tumour compartments, including negative regulators of mammalian target of rapamycin signalling such as SIRT1. Multiplexed immunohistochemistry confirmed that SIRT1 protein was expressed more in CD8high than in CD8low compartments. Further analysis of bulk and single-cell RNA sequencing data from melanoma tissue samples suggested the expression of SIRT1 by different lymphocyte subpopulations (CD8+ T cells, CD4+ T cells and B cells). Furthermore, we showed in vivo that pharmacological SIRT1 activation increased the immunological effect of α-PD-1 ICI against melanoma cells in mice, which was accompanied by an increase in T-cell infiltration and T-cell-related cytokines, including interferon (IFN)-γ, CCL4, CXCL9, CXCL10 and tumour necrosis factor-α. In silico analysis of large transcriptional data cohorts showed that SIRT1 was positively associated with the proinflammatory T-cell chemokines CXCL9, CXCL10 and IFN-γ, and prolonged overall survival of patients with melanoma.
Our study deciphers the proteomics landscape in human melanoma, providing important information on the tumour microenvironment and identifying SIRT1 as having important prognostic and therapeutic implications.
肿瘤微环境显著影响患者对免疫检查点抑制剂（ICI）治疗的临床反应，但对潜在的免疫调节蛋白质组仍缺乏全面了解。
解读可靶向的生物学过程，这些过程决定肿瘤浸润淋巴细胞（TiLs）作为ICI临床反应的细胞等效物。
我们通过结合显微镜、基质辅助激光解吸质谱成像和液相色谱 - 质谱以及计算数据挖掘，绘制了黑色素瘤中富含TiL与低TiL区域蛋白质的空间分布。在同基因小鼠模型中对沉默调节蛋白1（SIRT1）活性进行药理调节，以评估药理激活SIRT1在两种同基因黑色素瘤小鼠模型中的疗效，一种已知对α程序性细胞死亡蛋白1（PD - 1）敏感，另一种对α - PD - 1耐药。
空间蛋白质组学和基于基因本体的富集分析确定了145种以上在CD8高肿瘤区域富集的蛋白质，包括雷帕霉素信号通路哺乳动物靶点的负调节因子如SIRT1。多重免疫组织化学证实SIRT1蛋白在CD8高区域比在CD8低区域表达更多。对黑色素瘤组织样本的批量和单细胞RNA测序数据的进一步分析表明不同淋巴细胞亚群（CD8 + T细胞、CD4 + T细胞和B细胞）表达SIRT1。此外，我们在体内表明药理激活SIRT1增加了α - PD - 1 ICI对小鼠黑色素瘤细胞的免疫作用，这伴随着T细胞浸润和T细胞相关细胞因子的增加，包括干扰素（IFN） - γ、CCL4、CXCL9、CXCL10和肿瘤坏死因子 - α。对大型转录数据队列的计算机分析表明SIRT1与促炎T细胞趋化因子CXCL9、CXCL10和IFN - γ呈正相关，并延长了黑色素瘤患者的总生存期。
我们的研究解读了人类黑色素瘤的蛋白质组学格局，提供了关于肿瘤微环境的重要信息，并确定SIRT1具有重要的预后和治疗意义。
