title: The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects.
abstract: 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 determinedin vitroand in distinct human tumor modelsin vivoThe resultsin vitroindicated 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 modelsin vivoPretreatment 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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Dongya
authors.initials: D
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Ji
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Qingang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China. yayihou@nju.edu.cn niyanhong12@163.com.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ni
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China. yayihou@nju.edu.cn niyanhong12@163.com.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D008297:Male; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D020395:Receptors, Interleukin-7 / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000074322:Antineoplastic Agents, Immunological; D020395:Receptors, Interleukin-7; D051196:Toll-Like Receptor 3; D002945:Cisplatin