SUMO机械组件表达失调促进肺癌对抗PD-1免疫疗法的抗性，通过上调外周血淋巴细胞凋亡实现

Dysregulated gene expression of SUMO machinery components induces the resistance to anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes

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Frontiers in Immunology

影响因子:5.9

分区:医学2区 / 免疫学2区

发表日期:2024

作者: Ying Wang, Chao Sun, Mengmeng Liu, Panyang Xu, Yanyan Li, Yongsheng Zhang, Jing Huang

DOI: 10.3389/fimmu.2024.1424393

摘要

大部分肺癌患者在接受抗PD-1免疫疗法后表现出药物抗性，导致生存期缩短。既往研究提示甲基化等表观遗传异常与抗PD-1免疫反应密切相关，但SUMO化在抗PD-1抗体免疫抗性中的作用尚不清楚。本研究通过实时PCR分析了接受抗PD-1免疫疗法的肺癌患者外周血单个核细胞（PBMC）中15种SUMO机械组件的mRNA表达。根据mRNA水平的变化百分比，评估了SUMO机械组件表达与免疫治疗结局的关系，以及影响SUMO化的因素。在体外用不同浓度的2-D08（SUMO化的特异性抑制剂）处理PBMC，利用流式细胞术分析淋巴细胞亚群的活化和死亡率。基于三种SUMO机械组件（SUMO1、SUMO3和Ubiquitin-conjugating enzyme E2I, UBE2I）基因表达建立了一种预测方法，用于区分对PD-1抑制剂无反应的患者。此外，SUMO化调控失调组（变化百分比>100或-50至-100）中外周血淋巴细胞数量显著减少。体外研究证实，低水平SUMO化可提高T细胞和自然杀伤（NK）细胞的激活状态，但极低的SUMO化水平会增加淋巴细胞的死亡率。我们的研究表明，SUMO机械组件表达失调可能通过上调外周血淋巴细胞的死亡，促使肺癌抗PD-1免疫治疗产生抗性。这些数据或为预测免疫疗法疗效提供有效的血液生物标志物，并揭示了抗PD-1免疫抗性的新的调控机制。

Abstract

The majority of patients with lung cancer exhibit drug resistance after anti-PD-1 immunotherapy, leading to shortened patient survival time. Previous studies have suggested an association between epigenetic abnormalities such as methylation and clinical response to anti-PD-1 immunotherapy, while the role of SUMOylation in resistance to anti-PD-1 antibody immunotherapy is still unclear.Here, the mRNA expression of 15 SUMO machinery components in PBMC from lung cancer patients receiving anti-PD-1 immunotherapy were analyzed using real-time PCR. Base on the percentage change in mRNA levels, the relationship between the expression of SUMO machinery components and outcomes of anti-PD-1 immunotherapy, and the influencing factors of SUMOylation were evaluated. PBMC was treated with different concentrations of 2-D08 (a specific inhibitor of SUMOylation) in vitro, and analyzed the activation and the death rates of lymphocyte subsets by flow cytometry analysis.A predictive method, base on the gene expression of three SUMO machinery components (SUMO1, SUMO3 and UBE2I), were developed to distinguish non-responders to PD-1 inhibitors. Furthermore, the number of lymphocytes in peripheral blood significantly reduced in the dysregulated SUMOylation groups (the percentage change >100 or -50 ~ -100 groups). In vitro studies confirmed that lightly low SUMOylation level improved the activation status of T and NK lymphocytes, but extremely low SUMOylation level lead to the increased death rates of lymphocytes.Our findings implied that dysregulated gene expression of SUMO machinery components could induce the resistance of anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes. These data might provide effective circulating biomarkers for predicting the efficacy of anti-PD-1 immunotherapy, and uncovered a novel regulatory mechanism of resistance to anti-PD-1 immunotherapy.