Yang Wang, Chen Naifei, Li Lingyu, Chen Xiao, Liu Xiangliang, Zhang Yongfei, Cui Jiuwei
The Cancer Center of the First Hospital of Jilin University, Changchun, Jilin 130021, People's Republic of China.
Lung Cancer (Auckl). 2020 Sep 7;11:59-71. doi: 10.2147/LCTT.S262822. eCollection 2020.
Although -mutated patients generally do not benefit from checkpoint inhibitors (ICIs), some patients in the KEYNOTE-001 study consistently benefited from this treatment. This study investigated immune microenvironment characteristics to identify the subgroup of patients that may benefit from ICIs.
Using data from The Cancer Genome Atlas Program (TCGA) and Cancer Proteome Atlas, TMB and protein level of PD-L1 were explored in the patients with mutations and wild-type patients. Different patterns of mutations (according to EGFR co-mutation with different downstream pathway genesets) were used to group mutation population. Estimated infiltration analyses were used to explore changes in the immune microenvironment.
This study analyzed somatic mutation data from 1287 patients from five cohorts (TCGA, Broad, The Tumour Sequencing Project, Memorial Sloan Kettering Cancer Center, Catalogue Of Somatic Mutations In Cancer database). The probability of mutation was approximately 14.30% (184/1287) and the co-mutation rate was 11.41% (21/184) in patients with mutations. Glycosaminoglycan-related pathways were significantly upregulated in the mutant group. -mutated patients had lower TMB and PD-L1 protein levels than those in wild-type patients. Increase immature DCs infiltration and decreased NK CD56dim, T gamma delta, cytotoxic, and Th2 cell infiltration were the main immune changes in -mutated patients. Patients with -MAPK co-mutations had higher levels of TMB and PD-L1 protein expression. Meanwhile, the co-mutated patients had a similar immune microenvironment as that in wild-type patients.
In this study, we defined a subgroup of patients with -MAPK co-mutations. These co-mutated patients may benefit from ICI treatment.
尽管携带 突变的患者通常无法从检查点抑制剂（ICI）中获益，但KEYNOTE - 001研究中的一些患者持续从该治疗中受益。本研究调查了免疫微环境特征，以确定可能从ICI中获益的患者亚组。
利用癌症基因组图谱计划（TCGA）和癌症蛋白质组图谱的数据，在携带 突变的患者和野生型患者中探索肿瘤突变负荷（TMB）和程序性死亡受体配体1（PD - L1）的蛋白水平。根据 突变与不同下游通路基因集的表皮生长因子受体（EGFR）共突变情况，对 突变人群进行分组。采用估计浸润分析来探索免疫微环境的变化。
本研究分析了来自五个队列（TCGA、布罗德研究所、肿瘤测序项目、纪念斯隆凯特琳癌症中心、癌症体细胞突变目录数据库）的1287例患者的体细胞突变数据。携带 突变患者的 突变概率约为14.30%（184/1287），共突变率为11.41%（21/184）。 突变组中糖胺聚糖相关通路显著上调。携带 突变的患者的TMB和PD - L1蛋白水平低于野生型患者。未成熟树突状细胞浸润增加以及自然杀伤细胞CD56dim、γδT细胞、细胞毒性T细胞和辅助性T细胞2浸润减少是携带 突变患者的主要免疫变化。携带 -丝裂原活化蛋白激酶（MAPK）共突变的患者具有更高水平的TMB和PD - L1蛋白表达。同时，共突变患者的免疫微环境与野生型患者相似。
在本研究中，我们定义了一组携带 -MAPK共突变的患者亚组。这些共突变患者可能从ICI治疗中获益。
