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Ubiquitin-specific protease 1 facilitates tumor immune escape from natural killer cells and predicts the prognosis in small cell lung cancer

SHIQIN JIANG1,#, YICHUN TANG2,#, FENG MA3, YUCHUN NIU4,*, LEI SUN5,*
1 Department of Clinical Pharmacy, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, 518104, China
2 Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
3 Department of Oncology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China
4 Department of Radiation Oncology, The First People’s Hospital of Foshan, Foshan, 528000, China
5 Department of Oncology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523721, China
* Corresponding Author: YUCHUN NIU. Email: email; LEI SUN. Email: email

Oncology Research https://doi.org/10.32604/or.2024.046895

Received 18 October 2023; Accepted 03 April 2024; Published online 13 May 2024

Abstract

Background: Small cell lung cancer (SCLC) is commonly recognized as the most fatal lung cancer type. Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers, their benefits are limited to a minority of patients with SCLC. Objective: In the present study, novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated. Methods: We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC. The functional role of the key gene identified in SCLC was determined both in vitro and in vivo. Results: A significant correlation was observed between patient survival and CD56dim natural killer (NK) cell proportion. Furthermore, we noted that the hub gene ubiquitin-specific protease 1 (USP1) is closely correlated with both CD56dim NK cells and overall survival in SCLC. Bioinformatics analysis revealed that USP1 is upregulated in SCLC. In addition, gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses. By co-cultivating NK-92 cells with SCLC cells, we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition. Furthermore, using a nude-mice xenograft tumor model, we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers. Conclusions: Our study findings highlight the importance of NK cells in regulating SCLC. USP1 overexpression can inhibit NK cell-mediated immunity; therefore, USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.

Keywords

Ubiquitin-specific protease 1 (USP1); Natural killer (NK) cell; Small cell lung cancer; Prognosis; Immune escape

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