泛癌单基因突变与免疫治疗-实体瘤中PRKDC突变与免疫检查点抑制剂响应的关联研究

Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors6.574Mol Oncol . 2020 Jun 5. doi: 10.1002/1878-0261.12739. Online ahead of print.

Abstract

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild-type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8+ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild-type samples (P < 0.05). In ICI-treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255-0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715-0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.   

Keywords: PRKDC; DNA-PKcs; immune checkpoint inhibitors; tumor microenvironment; tumor mutation burden.

1.数据
（1） TCGA和Geneplus（一个中国泛癌人群数据集）中实体肿瘤的突变数据。
（2）TCGA中10种实体肿瘤的全外显子测序和mRNA表达数据。
（3）TCGA中胃、结直肠和子宫内膜肿瘤中微卫星稳定性信息，包括微卫星稳定(MSS)和微卫星不稳定(MSI)亚型。
（4）四套包含PRKDC突变与ICI治疗响应状态和生存时间的患者数据。
2. TCGA和Geneplus中PRKDC突变图谱
TCGA和Geneplus中PRKDC突变频率如图1A所示，突变位点分布如图1B所示。


图1. PRKDC突变图谱

3.在多种癌型中，PRKDC突变与肿瘤突变负荷（TMB）增加有关
为验证PRKDC突变与TMB的相关性，研究者对PRKDC突变和PRKDC野生型患者的TMB进行比较。在TCGA数据集中PRKDC突变频率最高的10种癌症中，具有PRKDC突变样本的TMB显著高于无PRKDC突变的样本（图2A）。另外，PRKDC突变组与错配修复（MMR）基因、POLE/D1、BRCA1/2突变组之间的TMB无显著差异，上述各组的TMB均高于非突变组（上述基因均未突变的患者，图2B)。并且，PRKDC突变患者更倾向于为高突变负荷患者（TMB-H，图2C）。在Geneplus中也可以观察到相似结果。

图2. PRKDC突变与TMB
4.PRKDC突变与CTL、NK细胞浸润和肿瘤微环境炎症特征基因的相关性研究
为进一步探究PRKDC突变对表型和免疫状态的影响，研究者们基于TCGA中的十种癌症数据集，对PRKDC突变组和PRKDC野生型患者的Hallmark基因集进行GSEA富集分析，富集结果如图3A所示，其中已有研究证实与免疫浸润，肿瘤微环境和免疫治疗效果密切相关的IFN-γ通路信号在PRKDC突变组中上调， TGF-β通路信号在PRKDC突变组中下调。

以往的研究表明，免疫细胞的存在，特别是肿瘤特异性T细胞和NK细胞浸润，与免疫检查点抑制剂（ICI）显著相关。在PRKDC突变样本中CD8 T细胞，趋化因子，免疫检查点，细胞毒性T细胞，和NK细胞中有多个相关免疫基因表达高于未突变组（图3B-C）。

图3. PRKDC突变状态与免疫细胞浸润
5. PRKDC突变与ICI响应
与之前研究一致，在包含突变信息的两套独立ICI治疗数据集中，PRKDC突变患者突变负荷更高（图4A-C），并且ICI治疗响应比例也高于野生型患者（图4D）。另外，在四套独立ICI治疗数据集中，PRKDC突变患者有更长的总生存时间或无进展生存时间（图4E-H），对ICI治疗响应程度更高。

图4. PRKDC突变与ICI响应
总结：

今天的文章是不是依旧很简单呢，从单个基因突变入手，研究多种癌型中PRKDC突变与免疫检查点抑制剂响应之间的关联。对免疫和ICI治疗感兴趣的小伙伴不妨关注下文章中的四套独立ICI治疗数据集，说不定就可以为你的工作锦上添花呢！

转自生信人

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