Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
Translational Radiobiology and Diagnostics Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland.
Sci Rep. 2022 Feb 28;12(1):3259. doi: 10.1038/s41598-022-07228-x.
Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.
化疗上调肿瘤细胞表面免疫检查点（IC）的表达，IC 内在信号赋予几种癌症类型（包括食管腺癌（OAC））对化疗的生存优势。然而，介导化疗诱导的 IC 上调的信号通路以及 IC 用于保护 OAC 细胞免受化疗的机制尚不清楚。纵向分析显示，FLOT 诱导的 OE33 OAC 细胞的 IC 上调可持续长达 3 周，在肿瘤细胞完全恢复后恢复到基线。促进生存的 MEK 信号介导了 FLOT 诱导的 PD-L1、TIM-3、LAG-3 和 A2aR 在 OAC 细胞上的上调，促进了更具免疫抵抗性的表型。单独使用 PD-1、PD-L1 和 A2aR 阻断剂可降低 OAC 细胞的活力、增殖并介导细胞凋亡。机制研究表明，阻断 PD-1 轴可降低干细胞样标志物 ALDH 和 DNA 修复基因的表达。重要的是，单独使用 PD-1、PD-L1 和 A2aR 阻断剂与 FLOT 联合使用可增强 OAC 细胞的细胞毒性。这些发现揭示了 IC 内在信号在 OAC 细胞中免疫独立功能的新机制，这对提高 OAC 一线 FLOT 化疗方案与 ICB 联合使用的疗效具有重要的临床意义，不仅可以增强抗肿瘤免疫，还可以抑制 IC 介导的促进肿瘤进展的关键癌症特征的促进作用。
