CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Plectin promotes an aggressive phenotype and represses cytotoxic T cell activity in pancreatic cancer.
Plectin promotes an aggressive phenotype and represses cytotoxic T cell activity in pancreatic cancer.
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我们的发现表明，plectin 是 PDAC 侵袭性疾病的生物标志物，高 plectin 表达与 T 细胞浸润减少相关，而抗 CSP 治疗可在体内恢复抗肿瘤免疫并减小肿瘤体积。这些发现提示，plectin 是一个新的治疗靶点，具有增强 PDAC 免疫应答并改善患者预后的潜力。
胰腺导管腺癌（PDAC）是一种临床结局极差的疾病，主要原因是延长生存的治疗手段有限。值得注意的是，PDAC表现出T细胞抑制性肿瘤微环境，而导致这一表型的潜在分子机制仍知之甚少。
利用TCGA-PAAD数据集，按PLEC表达对肿瘤样本进行分组，以评估患者生存情况以及与肿瘤发生增加相关的通路分析。使用tidyestimate和CIBERSORTx R包进行免疫浸润评估及后续免疫解卷积，并对人类PDAC样本进行免疫组织化学（IHC）以分析PLEC表达和免疫细胞浸润。分析来自229例PDAC患者的单细胞RNA-seq（scRNA-seq）数据，以研究PLEC高表达患者中的信号动态和免疫细胞浸润。通过在两种小鼠PDAC模型中使用针对细胞表面plectin（CSP）的单克隆抗体（mAb）提供功能验证，以检查肿瘤生长和免疫细胞亚群丰度的变化。
我们的研究揭示，在PDAC患者中，plectin高表达导致总体生存率更差，这与促肿瘤通路的激活和抗肿瘤免疫特征的减少相关。通过GSEA分析表明，PLEC高表达患者表现出侵袭性表型和促炎信号通路的抑制。PLEC高表达患者的免疫ESTIMATE评分显著降低，IHC和scRNA-seq分析显示，PLEC高表达肿瘤中抗肿瘤CD8+ T细胞减少。使用抗CSP mAb进行的体内分析显示，与IgG对照相比，肿瘤生长动力学降低，同时增殖和活化的细胞毒性CD8+ T细胞显著增加。当CD8+ T细胞被耗竭时，抗CSP介导的肿瘤抑制受到抑制，表明抗CSP治疗依赖于细胞毒性T细胞的功能。
Pancreatic adenocarcinoma (PDAC) is an abysmal disease with poor clinical outcomes, largely due to limited life-extending treatments. Notably, PDAC displays a T cell-suppressive tumor microenvironment, and the underlying molecular mechanisms that lead to this phenotype remain poorly understood.
Utilizing the TCGA-PAAD dataset, tumor samples were separated by PLEC expression to evaluate patient survival, and pathway analyses associated with increased tumorigenesis. Evaluation of immune infiltration and subsequent immune deconvolution was performed using tidyestimate and CIBERSORTx R packages and immunohistochemistry (IHC) from human PDAC samples was performed to analyze PLEC expression and immune cell infiltration. Single-cell RNA-seq (scRNA-seq) analysis from 229 PDAC patients was analyzed to investigate signaling dynamics and immune cell infiltration in PLEC High patients. Functional validation was provided using a monoclonal antibody (mAb) against cell surface plectin (CSP) in two murine PDAC models to examine changes in tumor growth and immune cell subset abundance.
Our studies revealed that high plectin expression results in an overall worse survival associated with activation of pro-tumorigenic pathways and decreased anti-tumor immune signature in PDAC patients. Analysis via GSEA indicates PLEC High patients display an aggressive phenotype and suppressed pro-inflammatory signaling pathways. Immune ESTIMATE scores were significantly decreased in PLEC High patients, and IHC and scRNA-seq analysis revealed that PLEC High tumors display a decrease in anti-tumor CD8 + T cells. In vivo analyses using an anti-CSP mAb revealed a reduction in tumor growth kinetics compared to IgG control corresponding with a significant increase in proliferating and activated cytotoxic CD8 + T cells. Anti-CSP-mediated tumor suppression was inhibited when CD8 + T cells were depleted, indicating that anti-CSP treatment is contingent on cytotoxic T cell functionality. DISCUSSION: Our findings identify plectin as a biomarker of aggressive disease in PDAC, with high plectin expression associated with decreased T cell infiltration, and anti-CSP treatment reinstates antitumor immunity and decreases tumor volume in vivo . These findings suggest that plectin is a novel therapeutic target with the potential to enhance immune responses in PDAC and improve patient outcomes.
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