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.

研究背景：激动型抗体（agonistic antibodies）联合免疫检查点抑制剂是肿瘤免疫治疗极具前景的研究方向。本研究旨在探究宫颈癌（CC）患者外周血与肿瘤组织中CD8+ T细胞上4-1BB、诱导性共刺激分子（ICOS）、CD28与程序性死亡受体1（PD-1）的共表达情况，重点关注4-1BB与PD-1的共表达水平与临床特征、预后及免疫治疗应答之间的关联，以期为宫颈癌免疫治疗提供宝贵的理论参考。
研究方法：本研究纳入50例初治确诊的宫颈癌患者。采用流式细胞术检测CD8+ T细胞上PD-1/4-1BB、PD-1/ICOS及PD-1/CD28的共表达水平。后续分析旨在探讨外周血与癌组织中该共表达水平的差异，以及共表达与患者临床特征之间的相关性。本研究同时利用基因表达综合数据库（Gene Expression Omnibus, GEO）数据集、癌症基因组图谱（The Cancer Genome Atlas, TCGA）队列、IMvigor210队列、BMS038队列及免疫表型评分（Immunophenoscores），探究PD-1/4-1BB与宫颈癌免疫微环境、预后、免疫治疗及药物敏感性之间的关联。
研究结果：宫颈癌患者CD8+肿瘤浸润淋巴细胞（Tumor-infiltrating Lymphocytes, TILs）上PD-1/4-1BB、PD-1/ICOS及PD-1/CD28的共表达水平显著高于外周血中的对应水平。临床特征分析显示，相较于PD-1/ICOS、PD-1/CD28、PD-1及4-1BB的单独表达，CD8+ TILs上PD-1/4-1BB的共表达与临床特征的相关性更为紧密。拟时序分析与细胞通讯分析结果表明，表达4-1BB与PD-1的细胞亚群之间存在密切关联。PD-1/4-1BB高、低共表达组患者的预后、肿瘤突变负荷、免疫景观及免疫治疗应答均存在统计学显著差异，且PD-1/4-1BB高共表达组患者更易从免疫治疗中获益。
研究结论：PD-1/4-1BB、PD-1/ICOS及PD-1/CD28在宫颈癌患者的CD8+ TILs上呈现高共表达特征，而在循环T细胞中表达水平较低。PD-1/4-1BB的共表达模式可有效预测免疫细胞浸润特征、预后及个体化免疫治疗策略，其有望成为宫颈癌联合免疫治疗的潜在靶点。