USP35 is a Potential Immunosuppressive Factor in Skin Cutaneous Melanoma

Qian Zhang; Yuan-Jie Liu; Jie-Pin Li; Shu-Hong Zeng; Hui Shen; Mei Han; Shun Guo; Shen-Lin Liu; Xi Zou

doi:10.2147/JIR.S362619

USP35 is a Potential Immunosuppressive Factor in Skin Cutaneous Melanoma

J Inflamm Res. 2022 May 24:15:3065-3082. doi: 10.2147/JIR.S362619. eCollection 2022.

Authors

Qian Zhang^#^{1

2}, Yuan-Jie Liu^#^{1

2}, Jie-Pin Li^{1

2

3}, Shu-Hong Zeng^{1

2}, Hui Shen³, Mei Han¹, Shun Guo^{1

2}, Shen-Lin Liu^{1

2}, Xi Zou^{1

2

4}

Affiliations

¹ Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China.
² No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People's Republic of China.
³ Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People's Republic of China.
⁴ Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, People's Republic of China.

^# Contributed equally.

Abstract

Background: As one of the most immunogenic malignancies, skin cutaneous melanoma (SKCM) is mainly characterized by a high prevalence in immune-compromised patients and a brisk lymphocyte infiltration in the tumor microenvironment (TME). However, to date, studies on deubiquitination in SKCM are still very limited.

Methods: Public data with regard to this study in SKCM patients were acquired from The Cancer Genome Atlas (TCGA) and the Gene-Expression Omnibus (GEO) databases. We stratified TCGA-SKCM cases using consensus clustering and identified independent prognostic factors in deubiquitinating enzymes encoding genes (DECGs) by LASSO-Cox analysis. USP35 transcriptome level was examined using public data and validated by Immunohistochemical (IHC) staining at the protein level. Enrichment analysis was used to explore the potential functions of USP35, and the TISCH database, providing further evidence at the single-cell level. The CIBERSORT algorithm was used to assess the relationship between USP35 and the immune microenvironment, and IHC was used to further evaluate the relationship between USP35 and immunotherapy response. Finally, we used the cBioPortal and the Methsurv database to analyze the significance of genomic alterations of USP35 in melanoma.

Results: Our results showed that DECGs can be effectively used to stratify SKCM patients, suggesting their potential significance in the development of SKCM. Furthermore, USP35 overexpression was significantly associated with an unfavorable prognosis. We further revealed that USP35 may be involved in the activation of TORC1 signaling. Most importantly, USP35 was found to be significantly associated with an immunosuppressive TME, both in terms of negative correlation with the abundance of infiltrating CD8+ T cells and in terms of the fact that patients with high USP35 expression may benefit less from immunotherapy than those with low USP35 expression.

Conclusion: Deubiquitinating enzymes are of great importance in the diagnosis and treatment of SKCM, and USP35 is an extremely promising target for immunotherapy.

Keywords: USP35; deubiquitinating enzymes; immunotherapy; skin cutaneous melanoma.

Grants and funding

The present study was supported by the Jiangsu Province Hospital of Chinese Medicine Peak Academic Talent Project (y2021rc19), the Advantageous Disciplines Program of Nanjing University of Chinese Medicine (ZYX03KF022 and ZYX03KF019), Science and Technology Project of Affiliated Hospital of Nanjing University of Chinese Medicine (Y2020CX62), State Administration of Chinese Medicine Project (20085-9-3), Jiangsu Provincial Science and Technology Department Project (BE2019771), Jiangsu Province Postgraduate Research Innovation Program Project (KYCX21-1677); Youth Science and Technology Project of Suzhou (No. KJXW2019059); the Suzhou Science and Technology Development Plan (No. SYSD2019006).