Higher preoperative serum levels of PD-L1 and B7-H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF-targeted therapy and unfavorable prognosis of renal cell carcinoma.
Higher preoperative serum levels of PD-L1 and B7-H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF-targeted therapy and unfavorable prognosis of renal cell carcinoma.
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DOI：
10.1002/cam4.754
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发表时间：
2016-08
期刊：
影响因子：
4
通讯作者：
Yoshida K
中科院分区：
文献类型：
--
作者：
Fukuda T;Kamai T;Masuda A;Nukui A;Abe H;Arai K;Yoshida K
肾细胞癌（RCC）是一种免疫原性和促血管生成的癌症。尽管抗血管内皮生长因子（VEGF）疗法在一些患者中取得了令人印象深刻的反应，但许多肿瘤最终对这种疗法产生了耐药性。B7家族分子如CTLA-4、PD-1和PD-L1是免疫检查点中的关键参与者，它们积极或消极地调节各种免疫反应。最近，基于用抗CTLA 4、抗PD-1或抗PD-L1抗体阻断免疫检查点的免疫疗法已被提出作为治疗转移性RCC的潜在新方法。肿瘤中PD-L1和B7-H4的高表达与RCC的不良预后相关，然而，在接受VEGF靶向药物的转移性RCC患者中，尚未阐明B7家族分子血清水平的临床影响。我们评估了RCC患者术前血清B7家族分子（包括CD 80、CD 86、PD-1、PD-L1、B7-H3、B7-H4和CTLA-4）和CD 28的水平，并确定其与各种临床病理特征的关系。术前血清PD-L1和B7-H4水平升高与肿瘤分化程度较低、侵袭和转移潜力较高、抗VEGF治疗反应较差和总生存期较短相关。这些发现表明，研究术前血清PD-L1和B7-H4水平不仅可用于评估RCC的生物学侵袭性，还可用于预测抗VEGF治疗的疗效和最终预后，这表明未来设计针对晚期RCC中免疫检查点的治疗的临床试验。
Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA‐4, PD‐1, and PD‐L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti‐CTLA4, anti‐PD‐1, or anti‐PD‐L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD‐L1 and B7‐H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF‐targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD‐1, PD‐L1, B7‐H3, B7‐H4, and CTLA‐4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD‐L1 and B7‐H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti‐VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD‐L1 and B7‐H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti‐VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs.