METHODS: This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance.
RESULTS: Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance.
CONCLUSIONS: These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.
方法:本研究评估了短期和长期TKI治疗对NSCLCTME的影响,特别针对表皮生长因子受体(EGFR)和间变性淋巴瘤激酶(ALK)突变。我们分析了免疫细胞组成的变化,细胞因子谱,和参与免疫逃避的关键蛋白质,如层粘连蛋白亚基γ-2(LAMC2)。我们还探讨了使用阿司匹林作为辅助疗法来调节TME和抵消TKI抵抗。
结果:短期TKI治疗可增强T细胞介导的肿瘤清除,减少免疫抑制M2巨噬细胞浸润,和下调LAMC2表达。相反,长期TKI治疗促进了免疫抑制性TME,有助于耐药性和促进免疫逃逸。在各种致癌突变中观察到差异反应,与EGFR靶向治疗相比,ALK靶向治疗引发更强的抗肿瘤免疫反应。值得注意的是,我们发现阿司匹林有可能通过调节TME和增强T细胞介导的肿瘤清除来克服TKI耐药.
结论:这些发现为TKI诱导的TME变化的动力学提供了新的见解,提高我们对NSCLC挑战的理解。该研究强调了TME在TKI耐药性中的关键作用,并表明辅助治疗,像阿司匹林,可能为增强TKI疗效和克服耐药性提供新的策略。