Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
Front Immunol. 2024 Aug 21;15:1444007. doi: 10.3389/fimmu.2024.1444007. eCollection 2024.
AXL receptor expression is proposed to confer immune-checkpoint inhibitor (ICI)-resistance in non-small cell lung cancer (NSCLC) patients. We sought to interrogate AXL expression in conjunction with mutational and tumor-microenvironmental features to uncover predictive mechanisms of resistance in ICI-treated NSCLC patients.
Tumor samples from 111 NSCLC patients treated with ICI-monotherapy were analyzed by immunohistochemistry for tumor- and immune-AXL expression. Subsets of patients were analyzed by whole-exome sequencing (n = 44) and imaging mass cytometry (n = 14). Results were related to ICI-outcome measurements.
Tumor-cell AXL expression correlated with aggressive phenotypic features including reduced OS in patients treated with ICIs ( = 0.04) after chemotherapy progression, but conversely associated with improved disease control ( = 0.045) in ICI-treated, PD-L1 high first-line patients. AXL+ immune-cell infiltration correlated with total immune-cell infiltration and improved overall outcomes (PFS: = 0.044, OS: = 0.054). Tumor-cell AXL-upregulation showed enrichment in mutations associated with PD-L1-upregulation and ICI-response such as and , as well as adverse mutations including and which associated with an immune-suppressed tumor phenotype and poor ICI prognosis particularly within chemotherapy-treated patients. Tumor mutational burden had no effect on ICI-outcomes and was associated with a lack of tumor-infiltrating immune cells. Spatial-immunophenotyping provided evidence that tumor-cell AXL-upregulation and adverse mutations modulate the tumor microenvironment in favor of infiltrating, activated neutrophils over anti-tumor immune-subsets including CD4 and CD8 T-cells.
Tumor-cell AXL-upregulation correlated with distinct oncotypes and microenvironmental immune-profiles that define chemotherapy-induced mechanisms of ICI-resistance, which suggests the combination of AXL inhibitors with current chemoimmunotherapy regimens can benefit NSCLC patients.
AXL 受体表达被认为赋予了非小细胞肺癌（NSCLC）患者对免疫检查点抑制剂（ICI）的耐药性。我们试图结合突变和肿瘤微环境特征来探究 AXL 表达，以揭示 ICI 治疗 NSCLC 患者耐药的预测机制。
通过免疫组化检测 111 例接受 ICI 单药治疗的 NSCLC 患者的肿瘤和免疫 AXL 表达。对部分患者进行了全外显子组测序（n = 44）和成像质谱细胞检测（n = 14）。结果与 ICI 结果测量相关。
肿瘤细胞 AXL 表达与侵袭性表型特征相关，包括化疗进展后接受 ICI 治疗的患者的 OS 降低（ = 0.04），但相反，在 ICI 治疗、PD-L1 高一线患者中，AXL+免疫细胞浸润与更好的疾病控制相关（ = 0.045）。肿瘤细胞 AXL 上调与总免疫细胞浸润和更好的总体结果（PFS： = 0.044，OS： = 0.054）相关。肿瘤细胞 AXL 上调显示与 PD-L1 上调和 ICI 反应相关的突变（如 和 ）以及不良突变（如 和 ）富集，这些突变与免疫抑制性肿瘤表型和较差的 ICI 预后相关，特别是在化疗治疗的患者中。肿瘤突变负担对 ICI 结果没有影响，与缺乏肿瘤浸润免疫细胞有关。空间免疫表型提供了证据，表明肿瘤细胞 AXL 上调和不良突变调节肿瘤微环境，有利于浸润、激活的中性粒细胞，而不是抗肿瘤免疫亚群，包括 CD4 和 CD8 T 细胞。
肿瘤细胞 AXL 上调与特定的癌型和微环境免疫特征相关，这些特征定义了化疗诱导的 ICI 耐药机制，这表明 AXL 抑制剂与当前的化疗免疫治疗方案联合使用可能使 NSCLC 患者受益。
