Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer.
Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer.
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DOI：
10.1158/1078-0432.ccr-16-2586
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发表时间：
2017-06-01
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影响因子：
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通讯作者：
Heymach JV
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作者：
Skinner HD;Giri U;Yang LP;Kumar M;Liu Y;Story MD;Pickering CR;Byers LA;Williams MD;Wang J;Shen L;Yoo SY;Fan YH;Molkentine DP;Beadle BM;Meyn RE;Myers JN;Heymach JV
头颈部鳞状细胞癌（HNSCC）的主要死亡原因是局部治疗失败。本研究的目的是用一种无偏见的方法来研究这种现象。我们利用通过重复暴露于辐射而呈现辐射抗性（RR）的HPV阴性细胞系、一组HPV阴性HNSCC细胞系和来自用放射治疗的患者的三组HPV阴性HNSCC肿瘤（n=68、97和114），并进行基因组、转录组和蛋白质组分析。与对照相比，RR细胞系表现出多种蛋白质的上调，包括Axl和PI 3激酶信号传导的激活增加以及PD-L1的表达增加。此外，Axl或PI 3激酶的抑制导致PD-Ll表达降低。当临床样品在单独的组群中进行RPPA和mRNA表达分析时，PD-L1与Axl和PI 3 K信号传导相关，并且与放疗后的局部失败显著相关。使用免疫组织化学检查第三个队列证实了这一发现。事实上，PD-L1高表达的肿瘤在放疗后的失败率为60%，70%和50%，而PD-L1低表达组为20%，25%和20%（p=0.01，1.9×10−3和9×10−4）。这一发现在所有组的多变量分析中仍然具有显著性。此外，PD-L1低/CD 8 + TIL高的患者没有局部衰竭或疾病导致的死亡（分别为p=5×10−4和p=4×10−4）。总之，我们的数据指向与辐射抗性高度相关的靶向Axl-PI 3激酶-PD-Ll轴。
The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach. We utilized HPV-negative cell lines rendered radiation resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n=68, 97, & 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic and proteomic analysis. RR cell lines exhibited up-regulation of several proteins compared to controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis in separate cohorts, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70% and 50% compared to 20%, 25% and 20% in the PD-L1 low expression group (p=0.01, 1.9×10−3 and 9×10−4 respectively). This finding remained significant on multivariate analysis in all groups. Additionally, those patients with PD-L1 low/CD8+TILs high had no local failure or death due to disease (p=5×10−4 and p=4×10−4 respectively). Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance.