Ileal Apoptosis and Microbiota Mediate Colon Cancer Treatment Efficacy

In colon cancer, standard-of-care cytotoxic chemotherapy with oxaliplatin can elicit an immune response against the cancer but can also affect crypt-derived intestinal epithelial cells (IEC), thus having an impact on the local microbiota. To investigate the effects of this, Roberti and colleagues started by examining the effect of oxaliplatin-based chemotherapy–induced ileal cell apoptosis in colon cancer. In patients with stage IV proximal colon cancer, ileal apoptosis was associated with substantial perturbation of the local microbiota and an enrichment of the tumor bed with follicular helper T (T_fh) cells, which may influence prognosis. These results were also seen in an oxaliplatin-treated syngeneic mouse model of microsatellite instability (MSI)-high colon cancer, in which ileal apoptosis was accompanied by alterations in the local microbiota and the balance between T_fh and T_h17 cells in the tumor-draining lymph nodes. Further confirming these findings, similar observations were made in other mouse models, and experiments in these mice also revealed that suppression of caspase-3– and caspase-7–mediated IEC apoptosis reduced protective oxaliplatin-driven immunosurveillance against colon cancer. T_fh cells were crucial for this effect, with oxaliplatin-induced IEC death stimulating the T_fh-cell response to colon cancer. Mechanistically, T_fh priming was dependent not only on ileal IEC-derived caspase-3 and caspase-7, but also on the cytokines IL1β and IL12 produced by BATF3⁺ conventional type 1 dendritic cells, and both the activation of the two caspases and the production of the two cytokines depended on the ileal microbiota. Preclinical data from experiments using organoids and mouse models revealed that ileal microbiota had a major role in the efficacy of oxaliplatin alone or with anti–PD-1 independently of MSI status, with the presence of certain commensal bacterial species enhancing the antitumor effects of these treatments. Collectively, these results suggest that ileal apoptosis and the local microbiota may substantially contribute to treatment efficacy in colon cancer and provide a mechanistic rationalization for this finding.

Roberti MP, Yonekura S, Duong CPM, Picard M, Ferrere G, Alou MT, et al. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nat Med 2020;26:919–31.

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