Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses.
Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses.
复制标题
吸收到细胞载体的TLR4激动剂的肿瘤内给药可改善抗肿瘤反应。
DOI：
10.1158/1078-0432.ccr-10-3262
复制
发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Kim YJ
中科院分区：
文献类型：
--
作者：
Davis MB;Vasquez-Dunddel D;Fu J;Albesiano E;Pardoll D;Kim YJ
由于TLR激动剂已被很好地表征为DC激活剂，我们假设将TLR 4激动剂混合到细胞载体中可以改善体内抗肿瘤反应。用LPS（一种TLR 4激动剂）配制分泌GM-CSF的全细胞肿瘤细胞载体（GVAX），并在三种不同的小鼠模型中测试其肿瘤内治疗功效。我们利用免疫组织化学、FACS、ELISPOT和体内CTL分析来评估肿瘤组织内的局部先天性免疫应答以及抗肿瘤T细胞应答的下游生成。与单独的GVAX相比，LPS吸收的GVAX的瘤内治疗显示出改善体内抗肿瘤反应的功效。在TLR 4信号传导受损的小鼠中不存在这种新型混合物的改善的抗肿瘤功效。在CT 26模型中，40-60%的小鼠显示出移植肿瘤的消退。当用CT 26肿瘤细胞再次攻击时，这些小鼠被证明对肿瘤具有免疫力。用TLR 4激动剂吸收的GVAX处理的肿瘤显示浸润的CD 4和CD 8 T细胞增加以及肿瘤组织中CD 86+细胞的数量增加。与单独的GVAX和模拟处理组相比，来自处理小鼠的引流淋巴结具有增加的活化的⑶ 86+、MHCII+和⑶ 80+树突状细胞的数量。ELISPOT分析和体内CTL分析显示，在用LPS吸收的GVAX处理的小鼠中，针对AH 1肿瘤抗原的特异性CTL的数目增加。可以使用基于细胞的载体靶向肿瘤微环境中APC上的TLR 4以改善体内抗肿瘤应答。
Since TLR agonists have been well characterized as DC activators, we hypothesized that the admixture of TLR4 agonist into a cellular vector could improve the anti-tumor response in vivo. GM-CSF secreting whole cell tumor cell vector (GVAX) was formulated with LPS, a TLR4 agonist, and its intratumoral therapeutic efficacy was tested in three different murine models. We utilized immunohistochemistry, FACS, ELISPOT, and in vivo CTL analysis to assess both local innate immune responses within the tumor tissue as well as the downstream generation of anti-tumor T-cell responses. Intratumoral treatment of LPS absorbed GVAX showed efficacy in improving an antitumor response in vivo in comparison to GVAX alone. Improved anti-tumor efficacy of this novel admixture was not present in TLR4 signaling impaired mice. In the CT26 model, 40-60% of the mice showed regression of the transplanted tumor. When rechallenged with CT26 tumor cells, these mice proved to be immunized against the tumor. Tumors treated with TLR4 agonist absorbed GVAX showed increased infiltrating CD4 and CD8 T-cells as well as increased numbers of CD86+ cells in the tumor tissue. Draining lymph nodes from the treated mice had enhanced number of activated CD86+, MHCII+, and CD80+ dendritic cells in comparison to GVAX alone and mock treated groups. ELISPOT assay and in vivo CTL assay showed increased numbers of CTLs specific for the AH1 tumor antigen in mice treated with LPS absorbed GVAX. TLR4 on APCs in the tumor microenvironment may be targeted using cell-based vectors for improved anti-tumor response in vivo.