Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer
Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer
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东亚非小细胞肺癌患者抗PD-1/PD-L1免疫治疗疗效的分子异质性与肿瘤免疫微环境相关
DOI：
10.20892/j.issn.2095-3941.2020.0121
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发表时间：
2020-08-01
影响因子：
5.5
通讯作者：
He, Jie
中科院分区：
文献类型：
--
作者：
Jin, Runsen;Liu, Chengming;He, Jie
目的：本研究的目的是研究肿瘤免疫微环境在肿瘤基因组学方面的差异，以及其对东亚非小细胞肺癌（NSCLC）患者的免疫治疗和反应的影响。研究方法：我们使用公开数据进行了综合分析，以确定东亚NSCLC患者中抗程序性死亡1（PD-1）/程序性死亡配体1（PD-L1）免疫治疗疗效与经典驱动癌基因突变之间的相关性。使用4项汇总和临床队列分析，基于PD-L1和CD 8+肿瘤浸润淋巴细胞（TIL）将驱动癌基因突变状态与肿瘤微环境相关联。还使用CIBERSORT算法建立了基因组NSCLC亚组的免疫浸润模式。结果如下：基于东亚NSCLC患者，TIDE分析显示，对于抗PD-1/PD-L1免疫治疗，表皮生长因子受体（EGFR）突变型和间变性淋巴瘤激酶（ALK）重排型肿瘤的疗效较差;然而，尽管Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变型肿瘤的疗效更好，但差异无统计学意义（EGFR：P = 0.037; ALK：P < 0.001; KRAS：P = 0.701）。汇总和临床队列分析表明肿瘤免疫微环境异质性与致癌模式相关。结果显示，PD-L1和TIL阳性KRAS突变型肿瘤的发生率明显较高，这表明KRAS突变可能驱动具有适应性免疫抵抗的炎症表型。然而，EGFR突变体或ALK重排组显示出显著更高比例的PD-L1-/TIL-肿瘤，表明免疫学无知的未发炎表型。值得注意的是，与三重野生型NSCLC肿瘤相似，EGFR L 858 R突变型肿瘤与炎性表型正相关，表明对抗PD-1/PD-L1免疫治疗的反应性（P < 0.05）。此外，CIBERSORT算法结果显示，EGFR突变和ALK重排肿瘤的特征在于富含静息记忆CD 4 + T细胞群（P < 0.001），以及缺乏CD 8 + T细胞（P < 0.01）和激活的记忆CD 4 + T细胞（P = 0.001）。结论：我们的研究强调了免疫异质性和免疫应答之间的复杂关系，在东亚NSCLC患者的致癌依赖。
Objective: The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics, as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer (NSCLC). Methods: We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients. Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs). Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm. Results: Based on East Asian NSCLC patients, TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy, epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged tumors yielded inferior responses; however, although Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors responded better, the difference was not statistically significant (EGFR: P = 0.037; ALK: P < 0.001; KRAS: P = 0.701). Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns. The results showed remarkably higher PD-L1- and TIL-positive KRAS-mutant tumors, suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance. However, the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors, suggesting an uninflamed phenotype with immunological ignorance. Notably, similar to triple wild-type NSCLC tumors, EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype, suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy (P < 0.05). Furthermore, the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+ T cell population (P < 0.001), as well as a lack of CD8+ T cells (P < 0.01), and activated memory CD4+ T cells (P = 0.001). Conclusions: Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.