The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line
The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line
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DOI：
10.1016/j.imlet.2017.07.005
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发表时间：
2017-10-01
影响因子：
4.4
通讯作者：
Yamaguchi, Ken
中科院分区：
文献类型：
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作者：
Akiyama, Yasuto;Nonomura, Chizu;Yamaguchi, Ken
STAT 3被认为是在肿瘤部位以各种方式介导肿瘤诱导的免疫抑制的关键分子，其通过源自肿瘤细胞的免疫调节细胞因子起作用。已经使用移植有人肿瘤细胞的裸鼠模型开发了特异性抗STAT 3抑制剂。本研究利用MHC-Ⅰ类和Ⅱ类基因同时缺失的免疫缺陷型NOG小鼠（dKO-NOG）建立人源化的免疫治疗模型，并将其应用于STAT 3抑制剂诱导的人源化免疫治疗中。我们通过使用人源化dKO-NOG小鼠研究了STAT 3抑制剂STX-0119对TMZ耐药（TMZ-R）U87胶质瘤肿瘤的免疫效果。我们比较了STX-0119在裸小鼠和人源化dKO-NOG小鼠模型之间的抗肿瘤作用。使用裸鼠模型的体内研究显示，与对照水平相比，STX-0119抑制TMZR U87肿瘤的生长，但未促进肿瘤浸润淋巴细胞（TIL）的积累。相比之下，STX-0119在人源化dKO-NOG小鼠中比在裸小鼠中更快速和更强地抑制肿瘤生长，并且在肿瘤中发现大量的TIL，主要由CD 8（+）T细胞和巨噬细胞组成。这些结果表明，STX-0119具有通过促进肿瘤部位的TIL积累而发生的抗肿瘤活性，并且人源化dKO-NOG小鼠系统可能是评估STAT 3抑制剂对人类系统的作用的有力工具。
STAT3 is considered to be a key molecule to mediating tumor-induced immunosuppression in various manners at tumor sites, by acting through immune-regulatory cytokines derived from the tumor cells. Specific anti-STAT3 inhibitors have been developed using nude mouse models transplanted with human tumor cells. However, mouse systems cannot accurately represent the human immune response induced by STAT3 inhibitors, and more humanized therapeutic model based on human immune cells and tumors are needed.In the present study, an immune-deficient NOG mouse with the deletion of both MHC-class I and class II genes, an MHC-double knockout mouse (dKO-NOG), was developed and used to establish humanized immunotherapeutic model. We investigated the immunological effect of the STAT3 inhibitor STX-0119 against TMZ-resistant (TMZ-R) U87 glioma tumors by using humanized dKO-NOG mice. We compared the anti-tumor effects of STX-0119 between the nude and humanized dKO-NOG mouse models. An in vivo study using the nude mouse model showed that STX-0119 inhibited the growth of TMZR U87 tumors, but accumulation of tumor infiltrating lymphocytes (TILs) were not promoted compared with the control levels. In contrast, STX-0119 inhibited tumor growth more rapidly and strongly in humanized dKO-NOG mice than in nude mice, and a large amount of TILs, mainly consisting of CD8(+) T cells and macrophages, were found in the tumors. These results suggest that STX-0119 has anti-tumor activity occurring through the promotion of TIL accumulation at the tumor site and that humanized dKO-NOG mouse system may be a powerful tool to evaluate the effects of STAT3 inhibitors on human systems.