Influence of USP15 and its derived-peptide on non-small cell lung cancer immune evasion via regulating PD-L1 stability.

“Influence of USP15 and its derived-peptide on non-small cell lung cancer immune evasion via regulating PD-L1 stability. Wu D(#)(1)(2)(3), Zeng T(#)(1)(2)(3), Lu RH(4), Zhu W(1)(3), Wen Q(2)(3), Mao XL(2)(3), Yu ZZ(2)(3), Lin GX(2)(3), Peng YX(2)(3), Lu SS(2)(3), Yi H(2)(3), Huang W(2)(3), Xiao ZQ(5)(2)(3), Peng J(5)(2)(3). Author information: (1)Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China. (2)Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan, China. (3)National Clinical Research Center of Geriatric Disorders (Xiangya Hospital), Xiangya Hospital, Central South University, Changsha, Hunan, China. (4)Department of Oral Medicine, Third Xiangya Hospital of Central South University, Changsha, Hunan, China. (5)Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China zhiqiangxiao@csu.edu.cn jinwupeng@csu.edu.cn. (#)Contributed equally BACKGROUND: Immune checkpoint inhibitors (ICIs) therapy targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) shows promising clinical benefits in non-small cell lung cancer (NSCLC). However, the relatively low response rate highlights the need to elucidate the regulatory mechanism of PD-L1 expression, and develop an alternative strategy to target PD-1/PD-L1 immune checkpoint pathway. Our study focuses on the role and mechanism of ubiquitin-specific protease 15 (USP15) and its derived peptide U10 on NSCLC immune evasion. METHODS: USP15 as PD-L1's deubiquitinase was identified by screening a human USP complementary DNA (cDNA) library. The role and mechanism of USP15 and its derived peptide U10 on PD-L1 stability in NSCLC cells were analyzed. T cell-mediated tumor cell killing activity and a syngeneic mouse NSCLC model were used to assess the influence of USP15 and U10 on NSCLC immune evasion. The antitumor effect of U10 in combination with PD-1 monoclonal antibody (mAb) via suppressing NSCLC immune evasion was also evaluated in mice. The expression and clinicopathological significance of USP15 and PD-L1 in cancer tissues were evaluated by immunohistochemistry. RESULTS: We identify USP15 as a novel deubiquitinase of PD-L1. Mechanistically, USP15 binds and stabilizes PD-L1 in NSCLC cells by inhibiting its ubiquitination and degradation. Functionally, USP15 inhibits T cell ability of killing NSCLC cells in vitro, and promotes NSCLC immune evasion in mice via decreasing the population and activation of CD8+ T cells in the tumor microenvironment. Based on the interacting regions of USP15 and PD-L1, we develop a 10 amino acid-long USP15-derived peptide U10, which successfully degrades PD-L1 via disrupting USP15 and PD-L1 interaction, dramatically suppresses NSCLC immune escape in vitro and in mice, and enhances the anti-NSCLC effect of PD-1 mAb in mice. Moreover, the expression levels of USP15 and PD-L1 are significantly higher in NSCLC than those in normal lung tissues and are positively correlated. The combination of USP15 and PD-L1 proteins was superior to individual proteins for predicting the efficacy of PD-1 mAb immunotherapy and patient prognosis in NSCLC. CONCLUSION: Our findings reveal a critical role for USP15 in PD-L1 stability regulation and NSCLC immune escape and develop a novel peptide as an alternative strategy for ICIs therapy of NSCLC. © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. Conflict of interest statement: Competing interests: None declared.”