Yi Ling, Yao Heng, Bai Zhexin, Xu Ziwei, Li Huimin, Cheng Yuting, Wang Chong
Department of Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Department of Minimally Invasive Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Cell Oncol (Dordr). 2025 Aug 27. doi: 10.1007/s13402-025-01101-5.
Neoadjuvant targeted therapy has emerged as a promising strategy for resectable non-small cell lung cancer (NSCLC). The analysis of the immune status of tumor microenvironment (TME) after targeted therapies is crucial for understanding the impact of targeted therapy on the TME and providing a basis for synergistic therapeutic approaches.
Forty-two patients with resectable lung adenocarcinoma (LUAD) were enrolled in this study, and multiplex immunofluorescence technology was used to explore the immune status of the TME after neoadjuvant targeted therapies.
Among the 42 patients, 9 (21.4%) and 33 (78.6%) had ALK and EGFR mutations, respectively, and TKIs were their first-line treatment. All patients received R0 resection, and thoracoscopic minimally invasive surgery were the predominant method. Seven (16.7%) patients reached pathological complete response (pCR), 4 (9.5%) get major pathological response (MPR), and these 11 patients were classified into the MPR group. The remaining 31 (73.8%) patients were non-MPR. The densities of CD8 + T cells (P < 0.001, P = 0.001), GZMB + CD8 + T cells (P = 0.004, P = 0.008), PD-1 + CD8 + T cells (P = 0.019, P = 0.036), macrophages (P = 0.020, P = 0.007), M1 macrophages (P = 0.010, P = 0.007), and ratios of CD8 + T/Treg (P < 0.001, P = 0.026) in TME were significantly higher in the MPR group and ALK mutation group compared with non-MPR and EGFR group. There were positive correlations between CD8 + T cells, PD-1 + CD8 + T cells (r = 0.397, P = 0.009) and GZMB + CD8 + T cells (r = 0.351, P = 0.023); CD8 + T cells and macrophages (r = 0.343, P = 0.026), and M1 macrophages (r = 0.412, P = 0.007). Additionally, eleven patients experienced disease progress during the follow-up period, and the Log-Rank test revealed that MPR patients tended to get longer PFS compared with non-MPR patients (P = 0.063), especially patients with higher densities of macrophages in the TME had significantly longer PFS (P = 0.042).
TKI-targeted therapy could reduce tumor burden, facilitating complete surgical resection. Patients with MPR and ALK mutations had a higher density of inflammatory immune cells in the TME and those with higher densities of macrophage had significantly longer PFS.
Not applicable.
新辅助靶向治疗已成为可切除非小细胞肺癌（NSCLC）的一种有前景的策略。分析靶向治疗后肿瘤微环境（TME）的免疫状态对于理解靶向治疗对TME的影响并为协同治疗方法提供依据至关重要。
本研究纳入42例可切除肺腺癌（LUAD）患者，采用多重免疫荧光技术探索新辅助靶向治疗后TME的免疫状态。
42例患者中，分别有9例（21.4%）和33例（78.6%）存在ALK和EGFR突变，酪氨酸激酶抑制剂（TKIs）为一线治疗。所有患者均接受R0切除，胸腔镜微创手术为主要手术方式。7例（16.7%）患者达到病理完全缓解（pCR），4例（9.5%）获得主要病理缓解（MPR），这11例患者被归为MPR组。其余31例（73.8%）患者为非MPR。与非MPR组和EGFR组相比，MPR组和ALK突变组TME中CD8+T细胞（P<0.001，P=0.001）、颗粒酶B（GZMB）+CD8+T细胞（P=0.004，P=0.008）、程序性死亡受体1（PD-1）+CD8+T细胞（P=0.019，P=0.036）、巨噬细胞（P=0.020，P=0.007）、M1巨噬细胞（P=0.010，P=0.007）的密度以及CD8+T/T调节性T细胞（Treg）比值（P<0.001，P=0.026）显著更高。CD8+T细胞、PD-1+CD8+T细胞（r=0.397，P=0.009）与GZMB+CD8+T细胞（r=0.351，P=0.023）之间；CD8+T细胞与巨噬细胞（r=0.343，P=0.026）以及M1巨噬细胞（r=0.412，P=0.007）之间存在正相关。此外，11例患者在随访期间出现疾病进展，对数秩检验显示MPR患者的无进展生存期（PFS）往往比非MPR患者更长（P=0.063），尤其是TME中巨噬细胞密度较高的患者PFS显著更长（P=0.042）。
TKI靶向治疗可减轻肿瘤负荷，有助于实现完整的手术切除。MPR和ALK突变患者TME中炎性免疫细胞密度较高，巨噬细胞密度较高的患者PFS显著更长。
不适用。
