A critical role for a peritumoral stromal reaction in the induction of T-cell migration responsible for interleukin-12-induced tumor regression

Interleukin (IL) 12 has been shown to elicit tumor regression when this cyt okine induces the migration of T cells to tumor sites. The present study in vestigates the role of a peritumoral stromal reaction in IL-12-induced T-ce ll 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 m igration nor tumor regression was observed in the Meth A and MCH-1-A1 model s. Stromal tissue containing neovascular blood vessels developed at the per itumoral area of the former two IL-12-responsive tumors but not at the peri tumoral 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 whi ch 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 trea tment. Histological analyses revealed that the parental cell Line had perit umoral stroma with intrastromal vessels but only a few vessels in tumor par enchyma, whereas the variant cell line showed no stroma but had abundant va sculature in the tumor parenchyma. Most importantly, only stromal vessels i n 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 CSA 1M-bearing mice migrated into the parental but not into the variant tumor m ass. Together with our previous finding that T-cell migration depends on th e VCAM-1/ICAM-1 adhesive interactions, the present results indicate a criti cal role for peritumoral stroma/stromal vasculature in the acceptance of tu mor-infiltrating T cells that is a prerequisite for IL-12-induced tumor reg ression.