Ileal Apoptosis and Microbiome Shape Immunosurveillance and Prognosis of Proximal Colon Cancer

The prognosis of colon cancer (CC) is governed by tumor infiltrating lymphocytes (TIL), in particular T follicular helper cells (TFH) and immunogenic chemotherapy. While gut commensals can promote colon carcinogenesis, their beneficial role in tumor immunosurveillance remains unclear. Here, we show that the ileal microbiota determines the balance between tolerogenic versus immunogenic cell death of crypt intestinal epithelial cells (IEC) of the ileum. Genetic ablation of caspase3/caspase7 or IL-1 in IEC reduced immunosurveillance against CC. Protective immune responses against CC were associated with reduced ileal microbial diversity and the presence of Erysipelotrichaceae and Negativicutes capable of releasing IL-1β from ileal IEC. Abundant TIL and favorable clinical outcome were correlated with increased crypt ileal apoptosis, a distinct ileal microbiome, loss of ileal immunity, as well as priming and recirculation of mesenteric and systemic TFH. These findings unveil the immunogenic role of ileal apoptosis in the prognosis of proximal CC.