Mammary tissue microenvironment determines T cell‐dependent breast cancer‐associated inflammation

Although the importance of the host tissue microenvironment in cancer progression and metastasis has been established, the spatiotemporal process establishing a cancer metastasis‐prone tissue microenvironment remains unknown. In this study, we aim to understand the immunological character of a metastasis‐prone microenvironment in a murine 4T1 breast tumor model, by using the activation of nuclear factor‐κb ( NF ‐κB) in cancer cells as a sensor of inflammatory status and by monitoring its activity by bioluminescence imaging. By using a 4T1 breast cancer cell line stably expressing an NF ‐κB/Luc2 reporter gene (4T1 NF ‐κB cells), we observed significantly increased bioluminescence approximately 7 days after metastasis‐prone orthotopic mammary fat‐pad inoculation but not ectopic s.c. inoculation of 4T1 NF ‐κB cells. Such in vivo NF ‐κB activation within the fat‐pad 4T1 tumor was diminished in immune‐deficient SCID or nude mice, or T cell‐depleted mice, suggesting the requirement of host T cell‐mediated immune responses. Given the fat‐pad 4T1 tumor expressed higher inflammatory mediators in a T cell‐dependent mechanism compared to the s.c. tumor, our results imply the importance of the surrounding tissue microenvironment for inflaming tumors by collaborating with T cells to instigate metastatic spread of 4T1 breast cancer cells.