KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma
KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma
复制标题
DOI：
10.1016/j.lungcan.2020.09.004
复制
发表时间：
2020-11-01
期刊：
影响因子：
5.3
通讯作者：
Wang, Yongsheng
中科院分区：
文献类型：
--
作者：
Gao, Ge;Liao, Weiting;Wang, Yongsheng
目的：抗程序性细胞死亡1（PD-1）/PD-1配体（PD-L1）免疫检查点抑制剂在KRAS突变患者中的疗效仍存在争议。此外，KRAS基因及其突变亚型是否以及如何影响免疫功能尚未明确。在这里，我们研究了一些重要的生物标志物的免疫治疗在特定的KRAS subtypes.Materials和方法的疗效：我们进行了生物信息学分析的体细胞突变数据，转录组测序数据和蛋白质组数据从癌症基因组图谱（TCGA）数据库。结果：567例肺腺癌（LUAD）患者中，KRAS基因突变率为26.29%，其中KRAS/TP 53共突变率为9.7%。我们观察到与野生型相比，KRAS突变组的肿瘤突变负荷（TMB）增加，而PD-L1表达和免疫细胞浸润无差异。更重要的是，TP 53和KRAS/TP 53共突变组不仅显著增加了肿瘤突变负荷，而且有更高的PD-L1蛋白水平和免疫细胞浸润。我们进一步关注KRAS突变亚型对免疫生物标志物的影响。肺腺癌组织中KRAS基因突变亚型以G12 C最多见（9.88%，56/567），其次为G12 V（5.82%，33/567）、G12 D（3.00%，17/567）、G12 A（3.00%，17/567）。其中G12 D突变是TMB明显降低的一种特殊突变亚型。当与TP 53共突变时，这种低突变负荷更显著。此外，我们的研究结果还显示，PD-L1蛋白表达水平和免疫细胞浸润显著降低KRAS G12 D/TP 53突变组中的活化的CD 4记忆T细胞、辅助性T细胞、M1巨噬细胞和NK细胞。KRAS G12 D/TP 53共突变驱动免疫抑制，可能是抗PD-1/PD-1的阴性预测生物标志物。肺腺癌患者中的L1免疫检查点抑制剂。
Objectives: The efficacy of anti- programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) immune checkpoint inhibitors remains controversial in patients with KRAS mutation. In addition, whether and how KRAS gene and its mutant subtypes might influence immunity has not been clarified yet. Here we examine some important biomarkers for the efficacy of immunotherapy in specific KRAS subtypes.Materials and Methods: We conducted a bioinformatics analysis on somatic mutations data, transcriptome sequencing data and proteomic data from The Cancer Genome Atlas (TCGA) database. CIBERSORT was used to provide an estimation of the abundances of immune cells using gene expression data.Results: From a cohort of 567 patients with lung adenocarcinoma (LUAD) based on TCGA, the overall mutation rate of KRAS was 26.29 %, including KRAS/TP53 co-mutation rate of 9.7 %. We observed increased Tumor mutation burden (TMB) in KRAS mutant group compared with wild type, while no difference in PD-L1 expression and immune cell infiltration. More importantly, TP53 and KRAS/TP53 co-mutation group not only significantly increased tumor mutation burden, but also had higher PD-L1 protein level and immune cell infiltration. We further focused on influence of KRAS mutant subtype on immune biomarker. The most prevalent mutant subtype of KRAS in lung adenocarcinoma was G12C(9.88 %,56/567), followed by G12 V(5.82 %,33/567), G12D(3.00 %,17/567), G12A(3.00 %,17/567), respectively. Among them, G12D mutation appeared to be a special mutant subtype with an obviously lower TMB. This low mutation load was more significant when co-mutation with TP53. Besides, our results also revealed significantly decreased expressions of PD-L1 protein level and immune cell infiltration (activated CD4 memory T cell, helper T cell, M1 macrophage and NK cell) in KRAS G12D/TP53 mutant group.Conclusion: KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma.