The Appendix Orchestrates T-Cell Mediated Immunosurveillance in Colitis-Associated Cancer

BACKGROUND & AIMS: Although appendectomy may reduce colorectal inflammation in patients with ulcerative colitis (UC), this surgical procedure has been suggested to be associated with an increased risk of colitis-associated cancer (CAC). Our aim was to explore the mechanism underlying the appendectomy-associated increased risk of CAC. METHODS: Five-week-old male BALB/c mice underwent ap-pendectomy, appendicitis induction, or sham laparotomy. They were then exposed to azoxymethane/dextran sodium sulfate (AOM/DSS) to induce CAC. Mice were killed 12 weeks later, and colons were taken for pathological analysis and immunohisto-chemistry (CD3 and CD8 staining). Human colonic tumors from 21 patients with UC who underwent surgical resection for CAC were immunophenotyped and stratified according to appen-dectomy status.RESULTS: Whereas appendectomy significantly reduced co-litis severity and increased CAC number, appendicitis induction without appendectomy led to opposite results. Intratumor CD3+ and CD8+ T-cell densities were lower after appendectomy and higher after appendicitis induction compared with the sham laparotomy group. Blocking lymphocyte trafficking to the colon with the anti-a4 beta 7 integrin antibody or a sphingosine-1-phosphate receptor agonist suppressed the inducing effect of the appendectomy on tumors' number and on CD3+/CD8+ intratumoral density. CD8+ or CD3+ T cells isolated from inflammatory neo-appendix and intravenously injected into AOM/DSS-treated recipient mice increased CD3+/CD8+ T-cell tumor infiltra-tion and decreased tumor number. In UC patients with a history of appendectomy, intratumor CD3+ and CD8+ T-cell densities were decreased compared with UC patients without history of appendectomy.CONCLUSIONS: In UC, appendectomy could suppress a major site of T-cell priming, resulting in a less efficient CAC immunosurveillance.

Automated summary

This study explored the mechanism underlying the increased risk of colorectal cancer associated with appendectomy in patients with ulcerative colitis. The results showed that appendectomy reduced colitis severity and increased cancer number, while appendicitis induction without appendectomy had the opposite effect. Blocking lymphocyte trafficking or injecting CD8+ or CD3+ T cells from the inflammatory neo-appendix suppressed the effects of appendectomy on tumor growth. In UC patients with a history of appendectomy, tumor-infiltrating T cell densities were decreased compared with those without appendectomy.