Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer

Toshiaki Miyazaki, Suyoun Chung, Hiroaki Sakai, Hirokazu Ohata, Yuuki Obata, Daisuke Shiokawa, Yukihiro Mizoguchi, Takashi Kubo, Hitoshi Ichikawa, Hirokazu Taniguchi, Kazunori Aoki, Tomoyoshi Soga, Hitoshi Nakagama, Koji Okamoto

研究成果: Article査読

2 被引用数 (Scopus)

抄録

The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient-derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR-mediated PD-L1 transactivation, and dampened immune responses; these changes were all abolished by PD-L1 knockout. In patient-derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD-L1, but also for cancer stem cell (CSC)-related characteristics and Wnt signaling. TDO2 was coexpressed with both PD-L1 and nuclear β-catenin in colon xenograft tumors, and the coexpression of TDO2 and PD-L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2-kynurenine-AHR pathway facilitates liver metastasis of colon cancer via PD-L1–mediated immune evasion and maintenance of stemness.

本文言語English
ページ(範囲)170-181
ページ数12
ジャーナルCancer science
113
1
DOI
出版ステータスPublished - 2022 1月

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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