Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

Abstract

The prognosis of colon cancer (CC) is dictated by tumor infiltrating lymphocytes, including T follicular helper cells (TFH), and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH-driven responses.Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IEC) and the accumulation of TFH cells in CC in patients and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IEC elicited PD1 + TFH in an IL-1R1 and IL-12 dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD1 blockade in CC, independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC. NMED-A98927: Roberti MP et al. In revision for Nature Medicine

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