Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People's Republic of China.
Nat Commun. 2024 Oct 18;15(1):8988. doi: 10.1038/s41467-024-53164-x.
Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC.
食管鳞状细胞癌（ESCC）具有高度异质性。我们对 ESCC 完整的分子和免疫景观的理解仍然有限，这阻碍了个性化治疗策略的发展。为了解决这个问题，我们对 120 名中国 ESCC 患者进行了基因组-转录组特征分析和人工智能辅助的组织病理学图像分析。在这里，我们展示了 ESCC 可以根据 bulk 和单细胞 RNA-seq 分为分化型、代谢型、免疫原性和干性亚型，每个亚型根据融合的深度学习模型都具有特定的分子和组织病理学特征。具有 WFDC2、SFRP1、LGR6 和 VWA2 等标志性基因的干性亚组预后最差，与免疫活性下调、EP300 突变/激活频率高、Wnt 信号通路功能突变富集以及肿瘤内异质性水平最高有关。通过转录组学和免疫组织化学进行的免疫分析显示，ESCC 细胞过度表达自然杀伤细胞标记物 XCL1 和 CD160 作为免疫逃逸。引人注目的是，XCL1 的表达也影响 ESCC 细胞对常见化疗药物的敏感性。这项研究为 ESCC 的治疗开辟了新途径，并提供了一个有价值的公共资源，以更好地理解 ESCC。
