Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.
Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.
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DOI：
10.18632/oncotarget.3081
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Huber PE
中科院分区：
文献类型：
--
作者：
Schölch S;Rauber C;Tietz A;Rahbari NN;Bork U;Schmidt T;Kahlert C;Haberkorn U;Tomai MA;Lipson KE;Carretero R;Weitz J;Koch M;Huber PE
除了局部细胞毒活性外，放疗还可引发局部和全身抗肿瘤免疫，这可通过免疫抑制剂（包括Toll样受体（TLR）7/8激动剂）增强。在这里，我们研究了TLR 7/8激动剂3 M-011（854 A）作为放疗佐剂增强树突状细胞（DC）抗原呈递活性的能力。联合治疗在结肠直肠癌和胰腺癌的皮下和原位小鼠模型中诱导了显著的局部和全身反应。体外细胞毒性试验以及单克隆抗体的体内耗竭实验将NK和CD 8 T细胞鉴定为介导治疗细胞毒性效应的细胞群，而在CD 11 c-DTR转基因小鼠中体内耗竭CD 11 c+树突状细胞（DC）显示DC是这种情况下的关键免疫枢纽。免疫反应的特异性通过ELISPOT测定来证实。因此，TLR 7/8激动剂似乎是放射治疗的有效佐剂，诱导对常规治疗释放的肿瘤抗原的强烈的局部和深刻的全身免疫应答。
In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy.
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DOI：
10.1158/1078-0432.ccr-12-0984
发表时间：
2012-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Vanpouille-Box C;Kawashima N;DiNapoli S;Babb JS;Formenti SC;Adams S;Demaria S
通讯作者：
Demaria S
影响因子：
15.9
作者：
Beignon, AS;McKenna, K;Bhardwaj, N
通讯作者：
Bhardwaj, N
影响因子：
5.8
作者：
Dumitru, Calin D.;Antonysamy, Mary A.;Gullikson, Gary W.
通讯作者：
Gullikson, Gary W.
影响因子：
5.4
作者：
KIESSLING, R;KLEIN, E;WIGZELL, H
通讯作者：
WIGZELL, H
影响因子：
20.3
作者：
Dovedi, Simon J.;Melis, Monique H. M.;Illidge, Timothy M.
通讯作者：
Illidge, Timothy M.