Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.
Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.
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DOI：
10.1371/journal.pone.0070417
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hodge JW
中科院分区：
文献类型：
--
作者：
Gameiro SR;Higgins JP;Dreher MR;Woods DL;Reddy G;Wood BJ;Guha C;Hodge JW
射频消融(RFA)是一种微创的能量传递技术，越来越多地用于局部治疗，以根除局部疾病。RFA诱导的肿瘤细胞坏死产生已知的诱导抗肿瘤免疫反应的肿瘤抗原的免疫原源。然而，RFA诱导的抗肿瘤免疫不足以控制转移进展。我们试图表征(A)RFA剂量在肿瘤免疫原性调节和产生免疫反应中的作用，以及(B)疫苗免疫治疗和RFA之间的潜在协同作用，目的是局部控制肿瘤和减缓全身进展。以表达肿瘤相关癌胚抗原(CEA)(MC38-CEA+)的小鼠结肠癌细胞为研究对象，观察亚致死性高温对细胞表型和CTL介导的杀伤敏感性的影响。在体内研究了RFA剂量对(A)MC38-CEA+肿瘤的表型和生长以及(B)诱导肿瘤特异性免疫反应的影响。最后，对分子特征以及RFA和表达CEA和三种共刺激分子(CEA/Tricom)的痘病毒疫苗之间的潜在协同作用进行了评估。在体外，MC38-CEA+细胞的亚致死温度(A)增加了细胞表面CEA、Fas和MHC-I类分子的表达，(B)使肿瘤细胞对CTL介导的溶解更敏感。在体内，RFA诱导了(A)肿瘤细胞表面的免疫原性调节，(B)增加了T细胞对CEA和其他TAA的反应。在CEA转基因小鼠中，RFA和疫苗联合治疗可诱导对CEA的CD4+T细胞免疫应答的协同增加，并同时根除CEA+和CEA-S.C.肿瘤。与单独使用RFA相比，顺序使用低剂量和高剂量RFA与疫苗一起使用可降低肿瘤复发。这些研究表明，在癌症患者中联合使用RFA和疫苗具有潜在的临床益处，并增加了对这一新的翻译范例的支持。
Radiofrequency ablation (RFA) is a minimally invasive energy delivery technique increasingly used for focal therapy to eradicate localized disease. RFA-induced tumor-cell necrosis generates an immunogenic source of tumor antigens known to induce antitumor immune responses. However, RFA-induced antitumor immunity is insufficient to control metastatic progression. We sought to characterize (a) the role of RFA dose on immunogenic modulation of tumor and generation of immune responses and (b) the potential synergy between vaccine immunotherapy and RFA aimed at local tumor control and decreased systemic progression. Murine colon carcinoma cells expressing the tumor-associated (TAA) carcinoembryonic antigen (CEA) (MC38-CEA+) were studied to examine the effect of sublethal hyperthermia in vitro on the cells’ phenotype and sensitivity to CTL-mediated killing. The effect of RFA dose was investigated in vivo impacting (a) the phenotype and growth of MC38-CEA+ tumors and (b) the induction of tumor-specific immune responses. Finally, the molecular signature was evaluated as well as the potential synergy between RFA and poxviral vaccines expressing CEA and a TRIad of COstimulatory Molecules (CEA/TRICOM). In vitro, sublethal hyperthermia of MC38-CEA+ cells (a) increased cell-surface expression of CEA, Fas, and MHC class I molecules and (b) rendered tumor cells more susceptible to CTL-mediated lysis. In vivo, RFA induced (a) immunogenic modulation on the surface of tumor cells and (b) increased T-cell responses to CEA and additional TAAs. Combination therapy with RFA and vaccine in CEA-transgenic mice induced a synergistic increase in CD4+ T-cell immune responses to CEA and eradicated both primary CEA+ and distal CEA– s.c. tumors. Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone. These studies suggest a potential clinical benefit in combining RFA with vaccine in cancer patients, and augment support for this novel translational paradigm.
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影响因子：
11.5
作者：
Chakraborty, Mala;Wansley, Elizabeth K.;Hodge, James W.
通讯作者：
Hodge, James W.
影响因子：
4
作者：
Hodge JW;Ardiani A;Farsaci B;Kwilas AR;Gameiro SR
通讯作者：
Gameiro SR
影响因子：
5.8
作者：
Ciesielski, Michael J.;Kozbor, Danuta;Fenstermaker, Robert A.
通讯作者：
Fenstermaker, Robert A.
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影响因子：
3.1
作者：
Hu, Minghua;Xia, MicroGene;Su, Lei
通讯作者：
Su, Lei
影响因子：
5.2
作者：
Akcakaya, Pinar;Ekelund, Susanne;Lui, Weng-Onn
通讯作者：
Lui, Weng-Onn