The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects
The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects
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TLR3 激动剂抑制药物外流并依次巩固低剂量顺铂化学免疫疗法，同时减少副作用
DOI：
10.1158/1535-7163.mct-16-0454
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发表时间：
2017-06-01
影响因子：
5.7
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
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作者：
Ding, Liang;Ren, Jing;Hou, Yayi
传统的最大剂量密度化疗使肿瘤患者在获得肿瘤缓解的同时，产生了化疗耐药，毒副作用增加。针对166例口腔鳞状细胞癌（OSCC）患者Toll样受体（TLR）-3广泛阳性表达的情况，我们提出了一种新的治疗方案，即序贯使用TLR-3激动剂聚肌苷-聚胞苷酸（PIC）和小剂量顺铂。顺铂的最佳剂量，PIC的新作用和联合化疗的副作用，在体外和不同的人类肿瘤模型在体内确定。体外结果表明，与PIC预培养下调药物转运蛋白（例如，P-gp和MRP-1），增加顺铂的胞浆滞留，并以TLR 3和caspase-3依赖的方式显著增强低剂量顺铂诱导的细胞死亡。同时，脾免疫细胞被激活，但免疫抑制性癌相关成纤维细胞（CAF）被抑制。这些发现在体内人肿瘤模型中得到证实。PIC预处理可促进低剂量顺铂滞留，减少骨髓抑制细胞（MDSC）、肿瘤相关巨噬细胞（TAM）和CAF，减轻OSCC模型中的不良反应，西妥昔单抗可安全地进一步增强其作用。这种策略也抑制了黑色素瘤和淋巴瘤的进展。此外，TLR 3负操纵炎症相关的长非编码RNA lnc-IL 7 R，其在该化疗期间上调。Inc-IL 7 R的敲低提高了化疗敏感性。总体而言，本研究为PIC/顺铂用于靶向肿瘤微环境并加强低剂量顺铂化疗提供了临床前新的指导，同时降低了副作用。Mol Cancer Ther; 16（6）; 1068-79.©2017 AACR.
The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine–polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo. The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3–dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo. Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068–79. ©2017 AACR.