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Background <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>P</i> &lt; 0.001, <i>P</i> = 0.001), GZMB + CD8 + T cells (<i>P</i> = 0.004, <i>P</i> = 0.008), PD-1 + CD8 + T cells (<i>P</i> = 0.019, <i>P</i> = 0.036), macrophages (<i>P</i> = 0.020, <i>P</i> = 0.007), M1 macrophages (<i>P</i> = 0.010, <i>P</i> = 0.007), and ratios of CD8 + T/Treg (<i>P</i> &lt; 0.001, <i>P</i> = 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 (<i>r</i> = 0.397, <i>P</i> = 0.009) and GZMB + CD8 + T cells (<i>r</i> = 0.351, <i>P</i> = 0.023); CD8 + T cells and macrophages (<i>r</i> = 0.343, <i>P</i> = 0.026), and M1 macrophages (<i>r</i> = 0.412, <i>P</i> = 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 (<i>P</i> = 0.063), especially patients with higher densities of macrophages in the TME had significantly longer PFS (<i>P</i> = 0.042).</p> Conclusion <p>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.</p> Clinical trial number <p>Not applicable.</p>

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Effect of neoadjuvant targeted therapy on the tumor microenvironment in resectable lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月27日

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  • Ling Yi,
  • Heng Yao,
  • Zhexin Bai,
  • Ziwei Xu,
  • Huimin Li,
  • Yuting Cheng,
  • Chong Wang

摘要

Background

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.

Methods

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.

Results

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).

Conclusion

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.

Clinical trial number

Not applicable.