Perforin deficiency attenuates inflammation and tumor growth in colitis‐associated cancer

Background: Patients with inflammatory bowel disease (IBD) have a markedly increased risk to develop colon cancer, but there are only limited data about the host antitumor response in such colitis‐associated cancer. In the present study we aimed at assessing the role of perforin‐dependent effector mechanisms in the immune response in a murine model of colitis‐associated colon cancer. Methods: Wildtype and perforin‐deficient mice were analyzed in a mouse model of colitis‐associated colon cancer using azoxymethane (AOM) and dextran sodium sulfate (DSS). Results: Tumors of wildtype mice showed infiltration of CD4+, CD8+ T cells, natural killer (NK) cells, high numbers of apoptotic cells, and expression of the transcription factor eomesodermin and cytotoxic effector proteins, suggesting a potential role of the antitumor immune response in AOM/DSS tumorigenesis. Furthermore, perforin deficiency resulted in reduced apoptosis of epithelial cells as compared to wildtype mice, whereas tumor infiltration by NK cells, CD8+, and CD4+ T cells was unchanged. However, perforin‐deficient mice surprisingly developed significantly fewer tumors than wildtype mice. Subsequent studies identified an important role of perforin in regulating colitis activity, as perforin deficiency caused a significant reduction of DSS colitis activity and proinflammatory cytokine production as compared to wildtype controls. Conclusions: Perforin is involved in both the antitumor immune response and the regulation of activity of mucosal inflammation in colitis‐associated cancer. Our data emphasize the possible consequences for therapeutic strategies targeting colitis‐associated colon cancer. (Inflamm Bowel Dis 2009;)

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