头颈癌的深度空间组学分析为替代性治疗靶点和治疗失败的合理性提供了理由。
Deep spatial-omics analysis of Head & Neck carcinomas provides alternative therapeutic targets and rationale for treatment failure.
发表日期：2023 Sep 13
作者：
Andrew Causer, Xiao Tan, Xuehan Lu, Philip Moseley, Siok M Teoh, Natalie Molotkov, Margaret McGrath, Taehyun Kim, Peter T Simpson, Christopher Perry, Ian H Frazer, Benedict Panizza, Rahul Ladwa, Quan Nguyen, Jazmina L Gonzalez-Cruz
来源：
GENES & DEVELOPMENT
摘要：
免疫检查点抑制剂（ICI）疗法在治疗转移性复发的头颈部咽喉鳞状细胞癌（OPSCCs）方面的成功有限（<30%）。我们假设肿瘤中的空间决定因素在癌症治疗结果中起着关键作用。在这里，我们描述了一个男性患者的病例，他被诊断为p16阳性的OPSCC并且有广泛的肺转移性疾病，在Nivolumab和Pembrolizumab/Lenvatinib治疗失败。通过对患者复发性OPSCC肿瘤进行先进的综合空间蛋白组学分析，我们证明：（i）基于空间转录组学（ST）的无偏组织聚类成功检测到肿瘤细胞，并使得对肿瘤前沿和核心中的增殖或耐药基因等表型特征进行研究成为可能；（ii）利用ST与空间蛋白组学成像相结合（SpiCi，空间蛋白质组学推导的细胞识别）可以解析肿瘤浸润免疫细胞的特征；（iii）ST数据允许基于其与其配对配体受体的相互作用来发现和排序与临床相关的替代药物。重要的是，当比较ICI治疗失败前后的OPSCC肿瘤的空间谱轮廓时，它们表现出高度相似的PD-1/PD-L1低表达和VEGFA高表达，这表明这些新的肿瘤并不是ICI耐药的产物，而是由于Lenvatinib剂量减少导致的并发症。我们的工作为在临床设置中引入空间组学提供了一条途径，以促进个体化治疗。© 2023. Nature Publishing Group UK.
Immune checkpoint inhibitor (ICI) therapy has had limited success (<30%) in treating metastatic recurrent Head and Neck Oropharyngeal Squamous Cell Carcinomas (OPSCCs). We postulate that spatial determinants in the tumor play a critical role in cancer therapy outcomes. Here, we describe the case of a male patient diagnosed with p16+ OPSCC and extensive lung metastatic disease who failed Nivolumab and Pembrolizumab/Lenvatinib therapies. Using advanced integrative spatial proteogenomic analysis on the patient's recurrent OPSCC tumors we demonstrate that: (i) unbiased tissue clustering based on spatial transcriptomics (ST) successfully detected tumor cells and enabled the investigation of phenotypic traits such as proliferation or drug-resistance genes in the tumor's leading-edge and core; (ii) spatial proteomic imagining used in conjunction with ST (SpiCi, Spatial Proteomics inferred Cell identification) can resolve the profiling of tumor infiltrating immune cells, (iii) ST data allows for the discovery and ranking of clinically relevant alternative medicines based on their interaction with their matching ligand-receptor. Importantly, when the spatial profiles of ICI pre- and post-failure OPSCC tumors were compared, they exhibited highly similar PD-1/PD-L1low and VEGFAhigh expression, suggesting that these new tumors were not the product of ICI resistance but rather of Lenvatinib dose reduction due to complications. Our work establishes a path for incorporating spatial-omics in clinical settings to facilitate treatment personalization.© 2023. Nature Publishing Group UK.