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Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy

Authors Fu C, Zhu X, Xu P, Li Y

Received 6 August 2018

Accepted for publication 11 September 2018

Published 15 January 2019 Volume 2019:12 Pages 609—617

DOI https://doi.org/10.2147/OTT.S182806

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Takuya Aoki


Changqing Fu,1 Xiaojue Zhu,2 Peiqi Xu,2 Yonghao Li2

1Clinical Laboratory, Zhangjiagang Fifth People’s Hospital, Suzhou University, Suzhou, Jiangsu 215621, People’s Republic of China; 2Clinical Laboratory, Zhangjiagang First People’s Hospital, Suzhou University, Suzhou, Jiangsu 215600, People’s Republic of China

Background: Effectiveness of clinical therapy such as chemotherapy for solid tumors is limited by acquired drug resistance and side effects. Available antitumor immunity methods showed promising prospect of cancer therapy. However, more drug targets for boosting antitumor immunity still need to be explored and selective and effective compounds are yet to be developed.
Purpose: To study the effect and possible mechanism of compound P5091, a selective USP7 inhibitor, on CT26 xenografts growth in mice.
Materials and methods: CT26 xenografts model was employed to examine the anti-tumor effect of P5091. RT-PCR and ELISA analysis were used to detect the level of IFN-γ, TNF-α and IL-10 in tumor tissue and serum, respectively. IFN-γ expression in CD4+ and CD8+ T cells was analyzed by intracellular stain. The level of FOXP3 in Treg cells was confirmed by intracellular stain and western blotting.
Results: Compound P5091, a selective USP7 inhibitor, was found to inhibit CT26 xenografts growth in mice, which is comparable to the effect of Anti-PD-1 antibody. RT-PCR analysis showed that P5091 treatment decreased IL-10 mRNA level in tumor tissue while elevated mRNA level of IFN-γ and TNF-α. Moreover, ELISA analysis manifested decreased of IL-10 and elevation of IFN-γ and TNF-α in serum from tumor bearing mice. Intracellular stain showed increased IFN-g expression both in CD4+ and CD8+ T cells after P5091 treatment. Furthermore, P5091 treatment caused FOXP3 loss in Treg cells decreased the proportion of Treg cells in tumor bearing mice.
Conclusion: Our study here showed that P5091 may be a candidate for cancer immunotherapy.

Keywords:
USP7, Treg, antitumor immunity, colon cancer

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