Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma.
Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-17-0256
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发表时间：
2017-10-01
期刊：
影响因子：
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通讯作者：
Jain RK
中科院分区：
文献类型：
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作者：
Liu H;Naxerova K;Pinter M;Incio J;Lee H;Shigeta K;Ho WW;Crain JA;Jacobson A;Michelakos T;Dias-Santos D;Zanconato A;Hong TS;Clark JW;Murphy JE;Ryan DP;Deshpande V;Lillemoe KD;Fernandez-Del Castillo C;Downes M;Evans RM;Michaelson J;Ferrone CR;Boucher Y;Jain RK
血管紧张素系统抑制物(ASIS)可以改善多种癌症类型的预后，包括胰腺导管腺癌(PDAC)。然而，还没有研究研究ASIS单独或联合辅助化疗对切除的PDAC患者的影响。我们对2006年1月至2010年12月在马萨诸塞州综合医院看到的ASI使用者和非使用者PDAC患者的记录进行了分析。为了确定PDAC中ASIS的机制，我们对切除的原发灶进行了RNA-SEQ。连续794名患者纳入研究。在接受手术的299名患者中，在单变量(中位数OS：36.3月比19.3个月，p=0.011)和调整后的多变量(HR，0.505；95%CI，0.339-0.750；p=0.001)分析中，ASI使用者的总生存期(OS)都较长。倾向分数调整分析还显示，慢性ASI用户的中位数OS较长。在未切除的患者中，ASIS的有益效果在局部晚期疾病患者中显著，但在转移性患者中则不显著。RNA-Seq分析显示，在ASI使用者(赖诺普利)的肿瘤中，细胞外基质正常化，参与PDAC进展的基因(如WNT和Notch信号)表达减少，与T细胞和抗原提呈细胞活性有关的基因表达增加。最后，ASI的长期使用与基因表达特征有关，该特征可预测在独立验证队列中的存活率。在非转移性PDAC患者中，长期使用ASI与较长的独立于化疗的OS有关。我们的RNA-Seq分析表明，ASI降低了癌细胞的恶性潜能，并刺激了原发PDAC的免疫微环境。
Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts. In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.