An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy.
An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy.
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DOI：
10.1371/journal.pone.0038111
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Guha C
中科院分区：
文献类型：
--
作者：
Zhang H;Liu L;Yu D;Kandimalla ER;Sun HB;Agrawal S;Guha C
最近的研究表明，由3′-3′-连接结构和dCp 7-deaza-dG双核苷酸组成的新一代合成的Toll样受体（TLR）9激动剂在小鼠和人中显示出比常规CpG寡核苷酸更强的免疫刺激作用。放射治疗（RT）提供了一种肿瘤抗原的来源，这些抗原从死亡的、受照射的肿瘤细胞中释放出来，而不会引起全身性免疫抑制。因此，我们研究了RT与设计师合成的TLR 9激动剂组合对肺癌小鼠模型中的抗肿瘤免疫、原发性肿瘤生长迟缓和转移的作用。用PBS、TLR 9激动剂、对照寡核苷酸、RT或RT和TLR 9激动剂的组合治疗携带足垫3LL肿瘤的C57 BL/6和同类B细胞缺陷小鼠（B-/-）。治疗后24 h，采用流式细胞术（FACS）和ELISA法检测脾细胞免疫表型及血清IFN-γ和IL-10水平。监测肿瘤生长、肺转移和存活率，并通过ELISA和免疫荧光法测定血清中的肿瘤特异性抗体和肿瘤组织中的沉积。TLR 9激动剂扩增并激活野生型小鼠中的B细胞和浆细胞样树突状细胞以及携带异位刘易斯肺腺癌（3LL）的B细胞缺陷（B-/-）小鼠中的自然杀伤DC（NKDC）。RT与TLR 9激动剂联合治疗抑制了野生型和B−/−小鼠中的3LL肿瘤生长。在野生型小鼠中发现了强烈的肿瘤特异性体液免疫应答（滴度：1/3200），并在肿瘤组织中沉积了小鼠IgG自身抗体，而RT+ TLR 9激动剂治疗后，B−/−小鼠中肿瘤浸润NKDC的数量增加。此外，接受联合治疗的小鼠比单药治疗组具有更少的肺转移和更高的存活率。TLR 9激动剂和RT的联合治疗诱导全身性抗肿瘤体液应答，增强NKDC的肿瘤浸润，减少肺转移并改善3LL癌症的鼠模型中的存活。
Recent studies have shown that a new generation of synthetic agonist of Toll-like receptor (TLR) 9 consisting a 3′-3′-attached structure and a dCp7-deaza-dG dinucultodie shows more potent immunostimulatory effects in both mouse and human than conventional CpG oligonucleotides. Radiation therapy (RT) provides a source of tumor antigens that are released from dying, irradiated, tumor cells without causing systemic immunosuppression. We, therefore, examined effect of combining RT with a designer synthetic agonist of TLR9 on anti-tumoral immunity, primary tumor growth retardation and metastases in a murine model of lung cancer. Grouped C57BL/6 and congenic B cell deficient mice (B−/−) bearing footpad 3LL tumors were treated with PBS, TLR9 agonist, control oligonucelotide, RT or the combination of RT and TLR9 agonist. Immune phenotype of splenocytes and serum IFN-γ and IL-10 levels were analyzed by FACS and ELISA, 24 h after treatment. Tumor growth, lung metastases and survival rate were monitored and tumor specific antibodies in serum and deposition in tumor tissue were measured by ELISA and immunofluorescence. TLR9 agonist expanded and activated B cells and plasmacytoid dendritic cells in wild-type mice and natural killer DCs (NKDCs) in B cell-deficient (B−/−) mice bearing ectopic Lewis lung adenocarcinoma (3LL). Combined RT with TLR9 agonist treatment inhibited 3LL tumor growth in both wild type and B−/− mice. A strong tumor-specific humoral immune response (titer: 1/3200) with deposition of mouse IgG auto-antibodies in tumor tissue were found in wildtype mice, whereas the number of tumor infiltrating NKDCs increased in B−/− mice following RT+ TLR9 agonist therapy. Furthermore, mice receiving combination therapy had fewer lung metastases and a higher survival than single treatment cohorts. Combination therapy with TLR9 agonist and RT induces systemic anti-tumoral humoral response, augments tumoral infiltration of NKDCs, reduces pulmonary metastases and improves survival in a murine model of 3LL cancer.
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DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
11.5
作者：
Aurisicchio, Luigi;Peruzzi, Daniela;La Monica, Nicola
通讯作者：
La Monica, Nicola
影响因子：
5.7
作者：
Chamoto, Kenji;Takeshima, Tsuguhide;Nishimura, Takashi
通讯作者：
Nishimura, Takashi
DOI：
10.1073/pnas.0705226104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Damiano, Vincenzo;Caputo, Rosa;Tortora, Giampaolo
通讯作者：
Tortora, Giampaolo
影响因子：
30.5
作者：
Latz, Eicke;Verma, Anjali;Golenbock, Douglas T.
通讯作者：
Golenbock, Douglas T.