Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Medical Oncology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Immunol. 2022 Sep 29;13:991091. doi: 10.3389/fimmu.2022.991091. eCollection 2022.
Immune checkpoint inhibitors (ICIs) are dramatically changing the treatment landscape of a variety of cancers. Nevertheless, the variability in ICI responses highlight the importance in identifying predictive biomarkers. PTPRD and PTPRT (PTPRD/PTPRT) are the phosphatases of JAK-STAT signaling, a critical pathway in anti-cancer immunity regulation. However, the pan-cancer association between PTPRD/PTPRT mutation and the efficacy of ICIs remains unclear across pan-cancer patients.
We analyzed the association between PTPRD/PTPRT mutations and patient outcomes using clinical data and genomic mutations from TCGA pan-cancer cohort. Furthermore, the ICI-treatment cohort was used to evaluate the relationship between PTPRD/PTPRT mutation and the efficacy of ICIs. Another ICIs-treatment cohort was used to validate the findings. The TCGA pan-cancer dataset was analyzed to explore the correlation between PTPRD/PTPRT mutations and immune signatures. Moreover, we combined four factors to construct a nomogram model that could be used to predict the survival of pan-cancer patients receiving ICI treatment. The calibration curves and area under the curve were applied to assess the performance of the model.
PTPRD/PTPRT mutations were shown to be associated with a worse prognosis in TCGA cohort ( < 0.05). In the Samstein cohort, prolonged overall survival (OS) was observed in PTPRD/PTPRT mutant cancers, compared with wild-type cancers (mOS: 40.00 vs 16.00 months, HR = 0.570, 95%CI: 0.479-0.679, < 0.0001). In the validation cohort, significant OS advantage was observed in PTPRD/PTPRT mutant patients (mOS: 31.32 vs 15.53 months, HR = 0.658, 95%CI: 0.464-0.934, = 0.0292). Furthermore, PTPRD/PTPRT mutations were associated with a higher tumor mutational burden, MSI score, and TCR score ( < 0.0001). Enhanced immune signatures were found in the PTPRD/PTPRT mutant cancers ( < 0.05). Finally, we successfully established a nomogram model that could be used to predict the survival of NSCLC patients who received ICI treatment. Based on the risk score of the model, patients in the low-risk group showed a better mOS than those in the high-risk group (mOS: 2.75 vs 1.08 years, HR = 0.567, 95%CI: 0.492-0.654; < 0.001).
PTPRD/PTPRT mutations may be a potential biomarker for predicting ICI treatment responsiveness in multiple cancer types.
免疫检查点抑制剂（ICIs）正在显著改变多种癌症的治疗格局。然而，ICI 反应的可变性突出了识别预测性生物标志物的重要性。PTPRD 和 PTPRT（PTPRD/PTPRT）是 JAK-STAT 信号通路的磷酸酶，该通路是抗癌免疫调节的关键途径。然而，PTPRD/PTPRT 突变与 ICI 疗效之间的泛癌相关性在泛癌患者中仍不清楚。
我们使用 TCGA 泛癌队列的临床数据和基因组突变分析了 PTPRD/PTPRT 突变与患者结局之间的关联。此外，ICI 治疗队列用于评估 PTPRD/PTPRT 突变与 ICI 疗效之间的关系。另一个 ICI 治疗队列用于验证研究结果。分析 TCGA 泛癌数据集以探讨 PTPRD/PTPRT 突变与免疫特征之间的相关性。此外，我们结合四个因素构建了一个列线图模型，可用于预测接受 ICI 治疗的泛癌患者的生存情况。应用校准曲线和曲线下面积来评估模型的性能。
在 TCGA 队列中，PTPRD/PTPRT 突变与预后较差相关（<0.05）。在 Samstein 队列中，与野生型癌症相比，PTPRD/PTPRT 突变癌症的总生存期（OS）延长（mOS：40.00 与 16.00 个月，HR=0.570，95%CI：0.479-0.679，<0.0001）。在验证队列中，PTPRD/PTPRT 突变患者的 OS 显著获益（mOS：31.32 与 15.53 个月，HR=0.658，95%CI：0.464-0.934，=0.0292）。此外，PTPRD/PTPRT 突变与更高的肿瘤突变负担、MSI 评分和 TCR 评分相关（<0.0001）。在 PTPRD/PTPRT 突变癌症中发现了增强的免疫特征（<0.05）。最后，我们成功建立了一个列线图模型，可用于预测接受 ICI 治疗的 NSCLC 患者的生存情况。基于模型的风险评分，低风险组患者的 mOS 优于高风险组（mOS：2.75 与 1.08 年，HR=0.567，95%CI：0.492-0.654；<0.001）。
PTPRD/PTPRT 突变可能是预测多种癌症类型 ICI 治疗反应的潜在生物标志物。
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