DataSheet_1_Increased co-expression of 4-1BB with PD-1 on CD8+ tumor-infiltrating lymphocytes is associated with improved prognosis and immunotherapy response in cervical cancer.pdf

BackgroundThe combination of agonistic antibodies with immune checkpoint inhibitors presents a promising avenue for cancer immunotherapy. Our objective is to explore the co-expression of 4-1BB, ICOS, CD28, with PD-1 on CD8+ T cells in the peripheral blood and tumor tissue of cervical cancer(CC) patients, with a specific focus on the association between the co-expression levels of 4-1BB with PD-1 and clinical features, prognosis as well as immunotherapy response. The goal is to offer valuable insights into cervical cancer immunotherapy.MethodsIn this study, 50 treatment-naive patients diagnosed with CC were enrolled. Flow cytometry was used to detect PD-1/4-1BB, PD-1/ICOS and PD-1/CD28 co-expression on CD8+ T cells. Subsequent analysis aimed to investigate the differential co-expression between peripheral blood and cancer tissue, and also the correlation between co-expression and clinical features in these patients. Gene Expression Omnibus (GEO) datasets, The Cancer Genome Atlas (TCGA) cohort, The IMvigor210 cohort, The BMS038cohort and Immunophenoscores were utilized to investigate the correlation between PD-1/4-1BB and the immune microenvironment, prognosis, immunotherapy, and drug sensitivity in cervical cancer.ResultsThe co-expression levels of PD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 on CD8+ tumor-infiltrating lymphocytes (TILs) were significantly higher in cervical cancer patients compared to those in peripheral blood. Clinical feature analysis reveals that on CD8+ TILs, the co-expression of PD-1/4-1BB is more closely correlated with clinical characteristics compared to PD-1/ICOS, PD-1/CD28, PD-1, and 4-1BB. Pseudo-time analysis and cell communication profiling reveal close associations between the subgroups harboring 4-1BB and PD-1. The prognosis, tumor mutation burden, immune landscape, and immunotherapy response exhibit statistically significant variations between the high and low co-expression groups of PD-1/4-1BB. The high co-expression group of PD-1/4-1BB is more likely to benefit from immunotherapy.ConclusionPD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 exhibit elevated co-expression on CD8+TILs of cervical cancer, while demonstrating lower expression in circulating T cells. The co-expression patterns of PD-1/4-1BB significantly contributed to the prediction of immune cell infiltration characteristics, prognosis, and tailored immunotherapy tactics. PD-1/4-1BB exhibits potential as a target for combination immunotherapy in cervical cancer.

背景：将拮抗性抗体与免疫检查点抑制剂相结合，为癌症免疫治疗提供了一条具有前景的途径。本研究旨在探讨在宫颈癌（CC）患者的外周血和肿瘤组织中，4-1BB、ICOS、CD28与PD-1在CD8+ T细胞上的共表达情况，并特别关注4-1BB与PD-1共表达水平与临床特征、预后以及免疫治疗反应之间的关联。研究目的在于为宫颈癌免疫治疗提供有价值的见解。
方法：在本研究中，纳入了50名未经治疗的宫颈癌患者。采用流式细胞术检测CD8+ T细胞上PD-1/4-1BB、PD-1/ICOS和PD-1/CD28的共表达。后续分析旨在探究外周血与肿瘤组织间的不同共表达情况，以及这些患者共表达与临床特征之间的相关性。本研究利用了Gene Expression Omnibus（GEO）数据集、The Cancer Genome Atlas（TCGA）队列、The IMvigor210队列、The BMS038队列和Immunophenoscores，以研究PD-1/4-1BB与宫颈癌免疫微环境、预后、免疫治疗和药物敏感性之间的相关性。
结果：与外周血相比，PD-1/4-1BB、PD-1/ICOS和PD-1/CD28在CD8+肿瘤浸润淋巴细胞（TILs）上的共表达水平在宫颈癌患者中显著升高。临床特征分析显示，在CD8+ TILs上，PD-1/4-1BB的共表达与临床特征的相关性较PD-1/ICOS、PD-1/CD28、PD-1和4-1BB更为密切。伪时间分析和细胞通讯分析揭示了携带4-1BB和PD-1的亚组之间存在紧密的关联。PD-1/4-1BB的高共表达组与低共表达组在预后、肿瘤突变负荷、免疫景观和免疫治疗反应方面存在统计学上的显著差异。PD-1/4-1BB的高共表达组更有可能从免疫治疗中获益。
结论：PD-1/4-1BB、PD-1/ICOS和PD-1/CD28在CD8+ TILs上表现出升高的共表达，而在循环T细胞中的表达较低。PD-1/4-1BB的共表达模式对预测免疫细胞浸润特征、预后以及定制免疫治疗策略具有重要意义。PD-1/4-1BB有望成为宫颈癌联合免疫治疗的一个潜在靶点。