Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.
Sci Rep. 2023 Sep 30;13(1):16468. doi: 10.1038/s41598-023-43122-w.
Tumor-associated high endothelial venules (TA-HEVs) mediate lymphocyte entry into tumors. Therefore, combined anti-angiogenesis therapy and programmed death-1 (PD-1) inhibitors might stimulate tumor immunity. This study will explore the TA-HEVs and real-world data of the combination therapy in non-small cell lung cancer (NSCLC). Firstly, we found a certain relationship between HEVs and immune effector cells by multiple immunofluorescence staining. We then analyzed the efficacy of immunotherapy combined with anti-angiogenesis therapy in advanced NSCLC patients by collecting real-world clinical data. Finally, we explored the predictive value of HEVs in combination therapy by analyzing pre-treatment pathological slides of patients with multiple immunofluorescence and RNA sequencing. Immunofluorescence staining of high endothelial venules (PNAd+) reveals that the frequency of HEVs is positively correlated with tumor-infiltrating stem-like CD8+ T cells (TCF-1+PD-1+) in the TME of advanced NSCLC patients (P = 0.0221). We retrospectively analyzed the efficacy of 96 patients with advanced NSCLC who received PD-1 inhibitors combined with anti-angiogenesis therapy in the real-world. The median PFS of patients combined with anti-angiogenesis therapy was longer than that of patients without anti-angiogenesis therapy (9.7 vs 8.6 months, P = 0.041). Multiple immunofluorescence staining of tumor biopsies before treatment from 14 patients with advanced NSCLC reveals that PNAd+ is predictive of better response and survival upon PD-1 inhibitors combined with anti-angiogenesis therapy (P = 0.0274). In addition, we collected peripheral blood from an effective group of patients for RNA sequencing and found that immune cells activation-related gene expression scores were higher. Combined anti-angiogenic and anti-PD-1 therapy stimulates tumor immunity through TA-HEVs formation. TA-HEVs not only mediate immune cell entry into tumors, but also are associated with the efficacy of PD-1 inhibitors and anti-angiogenesis therapy in NSCLC.
肿瘤相关高内皮静脉（TA-HEVs）介导淋巴细胞进入肿瘤。因此，联合抗血管生成治疗和程序性死亡受体-1（PD-1）抑制剂可能会刺激肿瘤免疫。本研究将探讨非小细胞肺癌（NSCLC）中的 TA-HEVs 和联合治疗的真实世界数据。首先，我们通过多重免疫荧光染色发现 HEVs 与免疫效应细胞之间存在一定的关系。然后，我们通过收集真实世界的临床数据，分析免疫治疗联合抗血管生成治疗在晚期 NSCLC 患者中的疗效。最后，我们通过对多位患者的肿瘤组织进行多重免疫荧光和 RNA 测序分析，探讨 HEVs 在联合治疗中的预测价值。高内皮静脉（PNAd+）的免疫荧光染色显示，HEVs 的频率与晚期 NSCLC 患者肿瘤微环境中浸润的肿瘤干细胞样 CD8+ T 细胞（TCF-1+PD-1+）呈正相关（P=0.0221）。我们回顾性分析了 96 例接受 PD-1 抑制剂联合抗血管生成治疗的晚期 NSCLC 患者的疗效。联合抗血管生成治疗的患者中位 PFS 长于未联合抗血管生成治疗的患者（9.7 与 8.6 个月，P=0.041）。对 14 例晚期 NSCLC 患者的肿瘤活检进行多重免疫荧光染色显示，PNAd+预测 PD-1 抑制剂联合抗血管生成治疗的反应和生存更好（P=0.0274）。此外，我们从有效的患者组收集外周血进行 RNA 测序，发现免疫细胞激活相关基因表达评分较高。联合抗血管生成和抗 PD-1 治疗通过 TA-HEVs 的形成刺激肿瘤免疫。TA-HEVs 不仅介导免疫细胞进入肿瘤，还与 NSCLC 中 PD-1 抑制剂和抗血管生成治疗的疗效相关。
