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USP14 Promotes Tryptophan Metabolism and Immune Suppression by Stabilizing IDO1 in Colorectal Cancer

ABSTRACT: IDO1 interacting proteins in two colorectal cancer cells and was subjected to beads, and the beads were washed by buffer and identified by mass spectrometry (MS)

ORGANISM(S): Homo Sapiens

SUBMITTER: Wenting Liao

PROVIDER: PXD033718 | iProX | Thu May 05 00:00:00 BST 2022

REPOSITORIES: iProX

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USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer.

Shi Dongni D Wu Xianqiu X Jian Yunting Y Wang Junye J Huang Chengmei C Mo Shuang S Li Yue Y Li Fengtian F Zhang Chao C Zhang Dongsheng D Zhang Huizhong H Huang Huilin H Chen Xin X Wang Y Alan YA Lin Chuyong C Liu Guozhen G Song Libing L Liao Wenting W

Nature communications 20220926 1

Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabi ...[more]

PMID: 36163134

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USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer.

Project description:Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.

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