Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-γ, and eradicate tumor cells
Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-γ, and eradicate tumor cells
复制标题
DOI：
10.4049/jimmunol.174.2.898
复制
发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Bankert, RB
中科院分区：
文献类型：
--
作者：
Broderick, L;Yokota, SJ;Bankert, RB
将小块人类原发性肺肿瘤活检组织植入 SCID 小鼠体内，产生了可行的皮下组织。异种移植物中的组织结构，包括肿瘤相关白细胞、肿瘤细胞和基质细胞，均保持功能状态。通过监测肿瘤体积的变化、基因表达模式、细胞耗竭分析以及功能阻断抗体的使用，我们之前在此异种移植模型中建立了外源性IL-12动员人类肿瘤相关白细胞通过依赖于IFN-γ的间接机制原位杀死肿瘤细胞。在这项研究中，免疫组织化学和 FACS 表征了 IL-12 诱导的肿瘤微环境中的早期细胞事件。到IL-12治疗后5天，组成型存在的人CD45(+)白细胞已经扩增并渗透到异种移植物的富含肿瘤的区域。治疗后两周，与对照处理的异种移植物中肿瘤进展和大多数人类白细胞逐渐丧失相比，人类白细胞扩张并且肿瘤完全消失。免疫组织化学分析表明，做出反应的人类白细胞主要是活化的或记忆的 T 细胞，还有少量能够产生 IFN-α 的 B 细胞、巨噬细胞、浆细胞和浆细胞样树突细胞。主要细胞群也通过 FACS 进行了表征，并显示出具有与 CD4(+) 效应记忆 T 细胞一致的表型。我们的结论是，人肺肿瘤的肿瘤微环境中存在静止的CD4+效应记忆T细胞，并且可以通过局部持续释放IL-12来重新激活，以增殖和分泌IFN-γ，从而根除肿瘤细胞。
The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-gamma. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45(+) leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-alpha. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4(+) effector memory T cell. We conclude that quiescent CD4(+) effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-gamma, leading to tumor cell eradication.