Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China; Institute of Thoracic Oncology, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Cancer Lett. 2024 Jul 1;593:216951. doi: 10.1016/j.canlet.2024.216951. Epub 2024 May 10.
Neoadjuvant immunotherapy represents promising strategy in the treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms underlying its impact on treatment sensitivity or resistance remain a subject of controversy. In this study, we conducted single-cell RNA and T/B cell receptor (scTCR/scBCR) sequencing of CD45 immune cells on samples from 10 patients who received neoadjuvant immunotherapy and chemotherapy. We also validated our findings using multiplexed immunofluorescence and analyzed bulk RNA-seq from other cohorts in public database. By integrating analysis of 87357 CD45 cells, we found GZMK + effector memory T cells (Tem) were relatively enriched and CXCL13+ exhausted T cells (Tex) and regulator T cells (Treg) decreased among responders, indicating a persistent anti-tumor memory process. Additionally, the enhanced presence of BCR expansion and somatic hypermutation process within TNFRSF13B + memory B cells (Bmem) suggested their roles in antigen presentation. This was further corroborated by the evidence of the T-B co-stimulation pattern and CXCL13-CXCR5 axis. The complexity of myeloid cell heterogeneity was also particularly pronounced. The elevated expression of S100A7 in ESCC, as detected by bulk RNA-seq, was associated with an exhausted and immunosuppressive tumor microenvironment. In summary, this study has unveiled a potential regulatory network among immune cells and the clonal dynamics of their functions, and the mechanisms of exhaustion and memory conversion between GZMK + Tem and TNFRSF13B + Bmem from antigen presentation and co-stimulation perspectives during neoadjuvant PD-1 blockade treatment in ESCC.
新辅助免疫治疗代表了治疗食管鳞癌（ESCC）的有前途的策略。然而，其对治疗敏感性或耐药性的影响的机制仍然存在争议。在这项研究中，我们对 10 名接受新辅助免疫治疗和化疗的患者的样本进行了 CD45 免疫细胞的单细胞 RNA 和 T/B 细胞受体（scTCR/scBCR）测序。我们还使用多重免疫荧光法验证了我们的发现，并分析了公共数据库中其他队列的批量 RNA-seq。通过整合对 87357 个 CD45 细胞的分析，我们发现应答者中 GZMK+效应记忆 T 细胞（Tem）相对富集，CXCL13+耗竭 T 细胞（Tex）和调节性 T 细胞（Treg）减少，表明持续存在抗肿瘤记忆过程。此外，TNFRSF13B+记忆 B 细胞（Bmem）中 BCR 扩增和体细胞超突变过程的增强存在表明它们在抗原呈递中的作用。这进一步得到了 T-B 共刺激模式和 CXCL13-CXCR5 轴的证据的证实。髓样细胞异质性的复杂性也尤为明显。通过批量 RNA-seq 检测到的 ESCC 中 S100A7 的高表达与耗竭和免疫抑制的肿瘤微环境有关。总之，这项研究揭示了免疫细胞之间以及它们功能的克隆动力学之间的潜在调节网络，以及在 ESCC 中接受新辅助 PD-1 阻断治疗时，从抗原呈递和共刺激的角度来看，GZMK+Tem 和 TNFRSF13B+Bmem 之间的耗竭和记忆转化的机制。
