Open AccessStemness and immune evasion conferred by the TDO2‐AHR pathway are associated with liver metastasis of colon cancer
Author(s) -
Miyazaki Toshiaki,
Chung Suyoun,
Sakai Hiroaki,
Ohata Hirokazu,
Obata Yuuki,
Shiokawa Daisuke,
Mizoguchi Yukihiro,
Kubo Takashi,
Ichikawa Hitoshi,
Taniguchi Hirokazu,
Aoki Kazunori,
Soga Tomoyoshi,
Nakagama Hitoshi,
Okamoto Koji
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15182
Subject(s) - metastasis , immune system , immunosurveillance , cancer research , cancer , kynurenine , cancer stem cell , liver cancer , colorectal cancer , wnt signaling pathway , biology , cancer cell , immunology , medicine , signal transduction , microbiology and biotechnology , hepatocellular carcinoma , tryptophan , biochemistry , amino acid
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.