SHIP1 is required for T cell surveillance of occult malignancies.

Abstract

SHIP1-deficient mice develop severe, transmural Crohn's-like ileitis and die prematurely. Recent analysis of a human Crohn's disease (CD) cohort revealed a significant subset of patients have severely reduced levels of SHIP1 expression suggesting SHIP1 deficiency leads to CD in both rodents and humans. The mucosal inflammatory disease that causes the premature death of SHIP1^-/- mice is a consequence of the requirement of SHIP1 expression for the survival of effector T cells in mucosal tissues. T cell specific ablation of SHIP1 expression in CD4CreSHIP1^flox/flox mice also results in Crohn's disease-like ileitis, but less severe than in their germline SHIP1^-/- counterparts due to the absence of a SHIP1 deficient neutrophil compartment. Consequently CD4CreSHIP1^flox/flox mice live much longer than their SHIP1^-/- counterparts. As Crohn's disease is associated with an increased risk of intestinal cancers in humans and that T cells are proposed to protect from occult malignancies, we hypothesized that CD4CreSHIP1^flox/flox mice would develop malignancies originating in the gut. Here we show that CD4CreSHIP1^flox/flox mice with ileitis develop spontaneous metastatic cancer originating in the small intestine, including widely disseminated histiocytic sarcoma and intestinal adenocarcinomas. Our findings demonstrate that T cells in the gut are essential to protect against occult intestinal cancers and that SHIP1 is essential for this function. These findings may aid our understanding of the increased susceptibility to intestinal cancer in IBD patients, and particularly since a significant subset of adult IBD patients have defective expression of SHIP1.