Sumo机械成分的基因表达失调，通过上调外周血淋巴细胞的死亡，诱导肺癌中抗PD-1免疫疗法的抗性
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
影响因子:5.90000
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
摘要
抗PD-1免疫疗法后，大多数肺癌患者表现出耐药性，导致患者的生存时间缩短。先前的研究表明，表观遗传异常（例如甲基化和对抗PD-1免疫疗法的临床反应）之间存在关联，而Sumoylation在抵抗抗PD-1抗体免疫疗法中的作用仍不清楚。在此仍然不清楚，从肺癌抗癌症患者中，PBMC中15 Sumo机械成分的mRNA表达受到了抗癌症抗pdime pscrime pdime pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd-pd antimentime。基于mRNA水平的百分比变化，EMO机械成分的表达与抗PD-1免疫疗法的结果与Sumoylation的影响因子之间的关系。 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.此外，外周血中的淋巴细胞数量显着降低了sumoylation组（百分比变化> 100或-50〜 -100组）。体外研究证实，略低的Sumoylation水平改善了T和NK淋巴细胞的激活状态，但极低的Sumoylation水平导致淋巴细胞的死亡率升高，您的发现表明，抗抗Pd-1免疫癌症的抗抑制作用的基因表达可能会诱导抗抗癌症的抑制作用，从而诱导抗PD-1免疫疗法的抗药性。淋巴细胞。这些数据可能提供有效的循环生物标志物来预测抗PD-1免疫疗法的功效，并发现了一种对抗PD-1免疫疗法的耐药性的新型调节机制。
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.