Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
Cancer Cell. 2023 Jul 10;41(7):1222-1241.e7. doi: 10.1016/j.ccell.2023.06.006.
For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.
对于无法手术的食管腺癌（EAC），确定最近批准的免疫化学疗法（ICI+CTX）治疗可能受益的患者仍然是一个关键挑战。我们使用独特设计的机会之窗试验（LUD2015-005）来解决这个问题，其中 35 名无法手术的 EAC 患者接受了为期四周的一线免疫检查点抑制剂治疗（ICI-4W），随后是 ICI+CTX。全面的生物标志物分析，包括生成食管癌的 65000 个细胞的单细胞 RNA 测序图谱，以及在 ICI-4W 期间对 EAC 的多时间点转录组分析，揭示了一种新型的 T 细胞炎症特征（INCITE），其上调与 ICI 诱导的肿瘤缩小相关。使用我们的单细胞图谱对预处理胃食管癌转录组进行反卷积，确定高肿瘤单核细胞含量（TMC）是 LUD2015-005 患者中总体生存率（OS）更高和独立队列中常见胃癌亚型对 ICI 反应的意外的 ICI+CTX 特异性预测因子。肿瘤突变负担是 LUD2015-005 OS 的另一个独立且附加的预测因子。TMC 可以改善胃食管癌中新兴的 ICI+CTX 治疗的患者选择。
