IDO1 and kynurenine pathway metabolites activate PI3K-Akt signaling in the neoplastic colon epithelium to promote cancer cell proliferation and inhibit apoptosis

The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer (CRC) growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established CRC cell lines containing β-catenin-stabilizing mutations, human CRC samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, kynurenine pathway metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes CRC progression. These findings may have implications for the rational design of new clinical trials which exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.

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