Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas
Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas
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DOI：
10.21873/anticanres.11714
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发表时间：
2017-07-01
影响因子：
2
通讯作者：
Aiba, Setsuya
中科院分区：
文献类型：
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作者：
Furudate, Sadanori;Fujimura, Taku;Aiba, Setsuya
背景/目的：肿瘤相关巨噬细胞（TAM）与脾脏CD 11b（+）细胞一起帮助维持肿瘤微环境。免疫调节化合物咪喹莫特（IQM）刺激先天免疫细胞，包括巨噬细胞，以诱导抗肿瘤作用。为了阐明IQM对肿瘤微环境的影响，我们使用B16 F10黑色素瘤模型研究了IQM在黑色素瘤生长过程中的免疫调节作用。材料与方法：为了阐明IQM对肿瘤微环境的免疫调节作用，我们使用B16 F10黑色素瘤模型分离CD 11b（+）TAM和脾CD 11b（+）细胞，并评价IQM的免疫调节作用。结果如下：IQM抑制B16 F10黑色素瘤的生长，同时肿瘤部位Foxp 3（+）调节性T细胞（TCLs）减少，这是由肿瘤源性和脾CD 11b（+）细胞下调CCL 22产生引起的。随后，我们研究了脾CD 11b（+）细胞对B16 F10黑色素瘤体内生长的抗肿瘤或肿瘤负载作用。未处理小鼠的脾CD 11b（+）细胞可加速B16 F10黑色素瘤生长，但IQM处理小鼠的脾CD 11b（+）细胞可抑制B16 F10黑色素瘤生长。与这些结果一致，在植入黑素瘤和来自局部IQM处理小鼠的脾CD 11b（+）细胞的小鼠肿瘤中，Foxp 3（+）T细胞显著降低。此外，肿瘤内施用抗CCL 22抗体通过减少肿瘤部位的Treg募集来抑制B16 F10黑素瘤生长。结论：IQM通过肿瘤相关巨噬细胞诱导抗肿瘤免疫应答的可能机制。
Background/Aim: Tumor-associated macrophages (TAMs), together with splenic CD11b(+) cells, help maintain the tumor microenvironment. The immunomodulatory compound imiquimod (IQM) stimulates innate immune cells, including macrophages, to induce antitumor effects. In order to elucidate the effects of IQM on the tumor microenvironment, we investigated the immunomodulatory effect of IQM during melanoma growth by using the B16F10 melanoma model. Materials and Methods: To elucidate the immunomodulatory effects of IQM on the tumor microenvironment, we isolated CD11b(+) TAMs and splenic CD11b(+) cells and evaluated the immunomodulatory effects of IQM, using the B16F10 melanoma model. Results: IQM suppressed B16F10 melanoma growth in parallel with reduction of Foxp3(+) regulatory T cells (Tregs) at the tumor site, caused by the down-regulation of CCL22 production by tumor-derived and splenic CD11b(+) cells. Subsequently, we investigated the antitumor or tumor-loading effects of splenic CD11b(+) cells on B16F10 melanoma growth in vivo. B16F10 melanoma growth was accelerated by splenic CD11b(+) cells from untreated mice, but was inhibited by splenic CD11b(+) cells from IQM-treated mice. Consistent with these results, Foxp3(+) Tregs were significantly decreased in tumors of mice implanted with both melanoma and splenic CD11b(+) cells from topical IQM-treated mice. Furthermore, intratumoral administration of anti-CCL22 antibody inhibited B16F10 melanoma growth by decreasing Treg recruitment at the tumor site. Conclusion: Our results suggest a possible mechanism for the antitumor immune response induced by IQM through tumor-associated macrophages.