Ogawa M, Umehara K, Yu W G, Uekusa Y, Nakajima C, Tsujimura T, Kubo T, Fujiwara H, Hamaoka T
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Cancer Res. 1999 Apr 1;59(7):1531-8.
Interleukin (IL) 12 has been shown to elicit tumor regression when this cytokine induces the migration of T cells to tumor sites. The present study investigates the role of a peritumoral stromal reaction in IL-12-induced T-cell migration. In the CSA1M and OV-HM tumor models, IL-12 treatment induced tumor regression that is associated with T-cell migration. Neither T-cell migration nor tumor regression was observed in the Meth A and MCH-1-A1 models. Stromal tissue containing neovascular blood vessels developed at the peritumoral area of the former two IL-12-responsive tumors but not at the peritumoral area of the latter two IL-12-unresponsive tumors. The significance of stroma development was investigated using a pair of tumor models (CSA1M and a subline derived from CSA1M designated the CSA1M variant), both of which exhibit the same tumor immunogenicity. In contrast to the parental CSA1M cell line, the variant cell line was not responsive to IL-12, and neither stroma development nor T-cell migration was observed, even after IL-12 treatment. Histological analyses revealed that the parental cell line had peritumoral stroma with intrastromal vessels but only a few vessels in tumor parenchyma, whereas the variant cell line showed no stroma but had abundant vasculature in the tumor parenchyma. Most importantly, only stromal vessels in the parental tumors expressed detectable and enhanced levels of vascular cell adhesion molecule 1 (VCAM-1)/ intercellular adhesion molecule 1 (ICAM-1) before and after IL-12 treatment, respectively. In contrast, parenchymal vasculature in the variant cell line failed to express VCAM-1/ICAM-1 even after IL-12 treatment. When transferred into recipient tumor-bearing mice, IL-12-stimulated T cells from the parental CSA1M-bearing or the variant CSA1M-bearing mice migrated into the parental but not into the variant tumor mass. Together with our previous finding that T-cell migration depends on the VCAM-1/ICAM-1 adhesive interactions, the present results indicate a critical role for peritumoral stroma/stromal vasculature in the acceptance of tumor-infiltrating T cells that is a prerequisite for IL-12-induced tumor regression.
白细胞介素（IL）12已被证明，当这种细胞因子诱导T细胞迁移至肿瘤部位时，可引发肿瘤消退。本研究调查了肿瘤周围基质反应在IL-12诱导的T细胞迁移中的作用。在CSA1M和OV-HM肿瘤模型中，IL-12治疗可诱导肿瘤消退，且这与T细胞迁移相关。在Meth A和MCH-1-A1模型中，未观察到T细胞迁移和肿瘤消退。在前两种对IL-12有反应的肿瘤的肿瘤周围区域，出现了含有新生血管的基质组织，而后两种对IL-12无反应的肿瘤的肿瘤周围区域则未出现。使用一对肿瘤模型（CSA1M和源自CSA1M的一个亚系，命名为CSA1M变体）研究了基质发育的意义，这两种模型均表现出相同的肿瘤免疫原性。与亲代CSA1M细胞系不同，变体细胞系对IL-12无反应，即使在IL-12治疗后，也未观察到基质发育和T细胞迁移。组织学分析显示，亲代细胞系的肿瘤周围有带基质内血管的基质，但肿瘤实质内只有少数血管，而变体细胞系则无基质，但肿瘤实质内有丰富的脉管系统。最重要的是，仅亲代肿瘤中的基质血管在IL-12治疗前后分别表达可检测到的且水平升高的血管细胞黏附分子1（VCAM-1）/细胞间黏附分子1（ICAM-1）。相比之下，即使在IL-12治疗后，变体细胞系的实质脉管系统也未能表达VCAM-1/ICAM-1。当将IL-12刺激的T细胞从携带亲代CSA1M或携带变体CSA1M的小鼠转移到受体荷瘤小鼠体内时，这些T细胞迁移至亲代肿瘤而非变体肿瘤块中。结合我们之前的发现，即T细胞迁移依赖于VCAM-1/ICAM-1黏附相互作用，目前的结果表明肿瘤周围基质/基质脉管系统在接受肿瘤浸润T细胞方面起关键作用，而这是IL-12诱导肿瘤消退的前提条件。
