Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinomaA finding with therapeutic potential
Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinomaA finding with therapeutic potential
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DOI：
10.1002/ijc.30429
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发表时间：
2017-01-01
影响因子：
6.4
通讯作者：
Rioux-Leclercq, Nathalie
中科院分区：
文献类型：
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作者：
Kammerer-Jacquet, Solene-Florence;Crouzet, Laurence;Rioux-Leclercq, Nathalie
透明细胞肾细胞癌（ccRCC）是一种侵袭性肿瘤，其特征在于在大多数情况下肿瘤抑制基因VHL失活。因此，VHL/HIF/VEGF通路在血管生成中起主要作用，并且目前被抗血管生成疗法靶向。耐药性的出现导致使用针对免疫检查点PD 1/PDL 1的靶向免疫疗法，以恢复抗肿瘤免疫应答。VHL状态和PD-L1表达之间的相关性研究很少。在这项研究中，我们回顾性分析了98例连续的ccRCC病例，并通过免疫组织化学（IHC）将PD-L1表达与临床数据（长达10年随访）、病理标准、VEGF、PAR-3、CAIX和PD-1表达以及完整的VHL状态（缺失、突变和启动子高甲基化）相关联。在69例ccRCC（70.4%）中观察到PD-L1表达，相应患者的预后较差，中位特异性生存期为52个月（p=0.03）。PD-L1表达与不良预后因素显著相关，如较高的ISUP核仁分级（p= 0.01）、诊断时的转移（p=0.01）、肉瘤样成分（p=0.04）、VEGF过表达（p=0.006）和胞质PAR-3表达（p=0.01）。PD-L1表达还与密集PD-1表达（p=0.007）和具有0或1个改变的ccRCC（非灭活VHL肿瘤; p=0.007）相关，在多变量分析后仍然显著（分别为p=0.004和p=0.024）。有趣的是，所有野生型VHL肿瘤（无VHL基因改变，11.2%）均表达PD-L1。在这项研究中，我们发现PD-L1表达与非灭活VHL肿瘤相关，特别是野生型VHL ccRCC，这可能会从抑制PD-L1/PD-1的治疗中获益。程序性死亡配体1（PD-L1）在透明细胞肾细胞癌（ccRCC）中异常表达，使其成为新免疫抑制剂的关键靶点。一般来说，当肿瘤对阻断由肿瘤抑制基因VHL失活（大多数ccRCC的共同特征）推动的血管生成过程的药物产生耐药性时，给予此类治疗。在这里，在接受根治性肾切除术的患者的ccRCC样本中，发现PD-L1表达与非灭活或野生型VHL ccRCC相关，但与灭活VHL疾病无关。此外，具有野生型VHL ccRCC和PD-L1表达的患者表现出相对较差的预后。
Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p=0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p=0.01), metastases at diagnosis (p=0.01), a sarcomatoid component (p=0.04), overexpression of VEGF (p=0.006), and cytoplasmic PAR-3 expression (p=0.01). PD-L1 expression was also associated with dense PD-1 expression (p=0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors; p=0.007) that remained significant after multivariate analysis (p=0.004 and p=0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.What's new? Programmed death-ligand 1 (PD-L1) is aberrantly expressed in clear cell renal cell carcinoma (ccRCC), making it a key target for new immunotherapeutic agents. In general, such therapies are administered when tumors become resistant to agents that block angiogenic processes fueled by inactivation of the tumor suppressor gene VHL, a feature common to most ccRCCs. Here, in ccRCC samples from patients who underwent radical nephrectomy, PD-L1 expression was found to be associated with non-inactivated or wild-type VHL ccRCC but not inactivated VHL disease. Moreover, patients with wild-type VHL ccRCC and PD-L1 expression exhibited relatively worse prognosis.