Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.
Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.
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发表时间：
1998-04
期刊：
影响因子：
11.2
通讯作者：
J. Lee;B. Fenton;C. Koch;J. Frelinger;E. Lord
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文献类型：
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作者：
J. Lee;B. Fenton;C. Koch;J. Frelinger;E. Lord
实体瘤内的微环境条件可能对肿瘤的生长及其对治疗的反应产生显着影响。肿瘤及其伴随的血管系统的无序生长往往会导致肿瘤区域缺氧（缺氧）。这些缺氧区域内的细胞对放疗和化疗等传统疗法更具抵抗力。在这里，我们检查了 EMT6 小鼠乳腺肿瘤的缺氧状态以及肿瘤不同区域内宿主细胞的位置，以确定这种微环境条件是否也可能影响它们被免疫系统识别的能力。通过流式细胞术对肿瘤内的缺氧进行定量，并使用针对 2-(2-硝基-1H-咪唑-1-基)-N-(2,2,3,3,3-五氟丙基)乙酰胺 (EF5)（一种选择性与缺氧细胞结合的硝基咪唑化合物）细胞加合物的单克隆抗体 (ELK3-51) 通过免疫组织化学进行可视化。使用单克隆抗体进行定量后，仅在氧合良好的区域发现了 Thy-1+ 细胞。这些 Thy-1+ 细胞的位置也在已转染白细胞介素 2 (IL-2) 基因的 EMT6 肿瘤中进行了检查，因为这些肿瘤包含数量大大增加的宿主细胞。令人惊讶的是，我们发现与亲代肿瘤相比，IL-2转染的肿瘤显着减少了缺氧。此外，使用荧光染料 Hoechst 33342（一种灌注血管的体内标记物），结合 PECAM-1 (CD31) 的免疫化学染色作为肿瘤脉管系统的标记物，我们发现 IL-2 转染的肿瘤中的血管化增加。因此，IL-2在肿瘤生长部位的表达不仅可以通过诱导肿瘤反应性CTL的产生，还可以通过增加活化T细胞向肿瘤的浸润来增强肿瘤免疫。
Microenvironmental conditions within solid tumors can have marked effects on the growth of the tumors and their response to therapies. The disorganized growth of tumors and their attendant vascular systems tends to result in areas of the tumors that are deficient in oxygen (hypoxic). Cells within these hypoxic areas are more resistant to conventional therapies such as radiation and chemotherapy. Here, we examine the hypoxic state of EMT6 mouse mammary tumors and the location of host cells within the different areas of the tumors to determine whether such microenvironmental conditions might also affect their ability to be recognized by the immune system. Hypoxia within tumors was quantified by flow cytometry and visualized by immunohistochemistry using a monoclonal antibody (ELK3-51) against cellular adducts of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide (EF5), a nitroimidazole compound that binds selectively to hypoxic cells. Thy-1+ cells, quantified using a monoclonal antibody, were found only in the well-oxygenated areas. The location of these Thy-1+ cells was also examined in EMT6 tumors that had been transfected with the gene for interleukin-2 (IL-2) because these tumors contain greatly increased numbers of host cells. Surprisingly, we found that IL-2-transfected tumors had significantly decreased hypoxia compared to parental tumors. Furthermore, using the fluorescent dye Hoechst 33342, an in vivo marker of perfused vessels, combined with immunochemical staining of PECAM-1 (CD31) as a marker of tumor vasculature, we found increased vascularization in the IL-2-transfected tumors. Thus, expression of IL-2 at the site of tumor growth may enhance tumor immunity not only by inducing the generation of tumor-reactive CTLs but also by allowing increased infiltration of activated T cells into the tumors.