Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.
Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.
复制标题
综合分析揭示了TKI诱导的EGFR/ALK阳性非小细胞肺癌肿瘤免疫微环境重塑。
DOI：
10.1080/2162402x.2021.1951019
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发表时间：
2021
期刊：
影响因子：
7.2
通讯作者：
Liao W
中科院分区：
文献类型：
--
作者：
Fang Y;Wang Y;Zeng D;Zhi S;Shu T;Huang N;Zheng S;Wu J;Liu Y;Huang G;Xue Y;Bin J;Liao Y;Shi M;Liao W
酪氨酸激酶抑制剂(TKI)在治疗表皮生长因子受体(EGFR)突变和间变性淋巴瘤激酶(ALK)重排的非小细胞肺癌(NSCLC)中起着关键作用。然而，TKIs对肿瘤免疫微环境的影响，尤其是反应者的动态变化，目前还没有完全阐明。因此，我们对TKI治疗前后EGFR/ALK阳性的非小细胞肺癌标本进行了RNA测序和全外显子组测序。结合新抗原和突变负荷估计，Xcell和单样本基因集浓缩分析(SsGSEA)用于评估肿瘤免疫细胞的浸润和活性。进一步利用加权基因相关网络分析和瓶颈法确定影响治疗相关免疫应答的HUB基因。我们发现TKI治疗重塑了治疗反应样本中的TIM。TKI治疗后，抗肿瘤细胞浸润率和细胞毒性显著增加，而ALK重排样本的抗原提呈受到限制。然而，在治疗前和治疗后的样本中，没有发现抗肿瘤细胞浸润或细胞毒性的显著变化。随后，我们发现，在TKI治疗后，神经丝重型(NEFH)突变在样本中丰富，并与中性粒细胞浸润减少有关。联合驱动TP53突变的EGFR突变型NSCLC和野生型TP53突变的ALK重排样本更容易被TKI诱导产生细胞毒作用。最后，HUB基因产生的免疫相关评分与免疫渗透、免疫激活以及良好的预后呈正相关。总之，TIM的动态变化为TKI-免疫联合治疗的药物选择和时机选择提供了线索。
Tyrosine kinase inhibitors (TKI) play a pivotal role in the treatment of non-small-cell lung cancer (NSCLC) with mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma kinase (ALK). However, the influences of TKIs on the tumor immune microenvironment (TIM), especially dynamic changes of responders, have not yet been fully elucidated. Therefore, RNA sequencing and whole-exome sequencing were performed on EGFR/ALK-positive NSCLC samples before and after TKI treatment. In combination with neoantigen and mutational-load estimations, xCell and single-sample gene set enrichment analysis (ssGSEA) were used to assess tumor immune-cell infiltration and activity. Furthermore, weighted-gene correlation network analysis and the bottleneck method were used to identify the hub genes that affected treatment-related immune responses. We found that TKI treatment remodeled the TIM in treatment-responsive samples. Profound increases in the rate of anti-tumor cell infiltration and cytotoxicity was observed following TKI treatment, while antigen presentation was limited in ALK-rearranged samples. However, no significant change in anti-tumor cell infiltration or cytotoxicity was found between pre-treatment and post-progression samples. Subsequently, we found that neurofilament heavy (NEFH) mutations were enriched in samples after TKI treatment and were associated with reduced neutrophil infiltration. The cytotoxicity of EGFR-mutant NSCLCs with co-driver TP53 mutation and ALK-rearranged samples with wild-type TP53 seems to be more easily induced by TKI. Finally, the immune-associated score generated by hub genes was positively correlated with immune infiltration, immune activation, and a favorable prognosis. In conclusion, the dynamic changes in the TIM provide clues to drug selection and timing for TKI-immunotherapy combinations.