Resolving tissue-level proteomic complexity in cutaneous squamous cell carcinoma (cSCC) with ultra high-plex spatial profiling

Cutaneous squamous cell carcinoma (cSCC) represents a major global health burden. Immune-checkpoint inhibitors (ICIs) are the primary treatment for advanced cSCC with durable responses. However, resistance to ICI is associated with a poor prognosis. More translational methods to profile the tumour microenvironment (TME) are needed. In this study, we demonstrate proof-of-concept for high-plex spatial proteomics 1116 proteins (GeoMx Discovery Protein Atlas, Bruker Spatial Biology) to profile 190 pathology-reviewed, consecutively gridded, tissue-compartments across the tumour and stromal regions revealing expression profiles underscored by metabolic and immunological activity. These signatures differentiate immunocompetent and immunocompromised cSCC patients by varying immune competency, including type I interferon signalling. Taken together, this study demonstrates utility for discovery spatial proteomics in a translationally focussed setting for cSCC.

皮肤鳞状细胞癌（Cutaneous squamous cell carcinoma, cSCC）是一类造成重大全球健康负担的疾病。免疫检查点抑制剂（immune-checkpoint inhibitors, ICIs）是晚期皮肤鳞状细胞癌的一线治疗手段，可带来持久的临床应答。然而，免疫检查点抑制剂耐药与不良预后密切相关，当前亟需更多可用于解析肿瘤微环境（tumour microenvironment, TME）的转化研究方法。本研究验证了覆盖1116种蛋白质的高多重空间蛋白质组学技术的概念可行性，采用布鲁克空间生物学的GeoMx发现蛋白质组图谱平台，对190个经病理学审核、连续网格化的肿瘤及间质区域组织分区进行表征，揭示了以代谢与免疫活动为核心特征的表达谱。这些特征标签可通过免疫状态差异区分免疫健全与免疫缺陷的皮肤鳞状细胞癌患者，其中涵盖I型干扰素信号通路相关特征。综上，本研究证实了以转化研究为导向的空间蛋白质组学发现技术在皮肤鳞状细胞癌研究中的应用价值。