Wang Xiaoyan, Wu Bingchen, Yan Zhengqing, Wang Guoqiang, Chen Shiqing, Zeng Jian, Tao Feng, Xu Bichun, Ke Honggang, Li Mei
Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, China.
Department of Oncology, Hospital of Chinese Medicine of Changxing County, Huzhou, China.
Front Oncol. 2021 May 27;11:650122. doi: 10.3389/fonc.2021.650122. eCollection 2021.
The common gamma receptor-dependent cytokines and their JAK-STAT pathways play important roles in T cell immunity and have been demonstrated to be related with response to immune checkpoint blockades (ICBs). PTPRD and PTPRT are phosphatases involved in JAK-STAT pathway. However, their clinical significance for non-small cell lung cancer (NSCLC) treated with ICBs is still unclear. Genomic and survival data of NSCLC patients administrated with anti-PD-1/PD-L1 or anti-CTLA-4 antibodies (Rizvi2015; Hellmann2018; Rizvi2018 Samstein2019) were retrieved from publicly accessible data. Genomic, survival and mRNA data of 1007 patients with NSCLC were obtained from The Cancer Genome Atlas (TCGA). mutation was significantly associated with better progression-free survival (PFS) in three independent Rizvi2015, Hellmann2018 and Rizvi2018 cohorts. The median PFS for mutant-type . wild-type NSCLC patients were not reached . 6.3 months (Rizvi2015, HR = 0.16; 95% CI, 0.02-1.17; P=0.03), 24.0 . 5.4 months (Hellmann2018, HR, 0.49; 95% CI, 0.26-0.94; P=0.03), 5.6 . 3.0 months (Rizvi2018, HR = 0.64; 95% CI, 0.44-0.92; P=0.01) and 6.8 . 3.5 months (Pooled cohort, HR, 0.54; 95% CI, 0.39-0.73; P<0.0001) respectively. mutation was an independent predictive factor for PFS in pooled cohort (P = 0.01). Additionally, mutation associated with better overall survival (OS) in Samstein2019 cohort (19 . 10 months, P=0.03). While similar clinical benefits were not observed in patients without ICBs treatment (TCGA cohort, P=0.78). In the further exploratory analysis, mutation was significantly associated with increased tumor mutation burden and higher mRNA expression of JAK1 and STAT1. Gene Set Enrichment Analysis revealed prominent enrichment of signatures related to antigen processing and presentation in patients with mutation. This work suggested that mutation might be a potential positive predictor for ICBs in NSCLC. These results need to be further confirmed in future.
常见的γ受体依赖性细胞因子及其JAK-STAT信号通路在T细胞免疫中发挥重要作用，并且已被证明与免疫检查点阻断（ICB）反应相关。PTPRD和PTPRT是参与JAK-STAT信号通路的磷酸酶。然而，它们在接受ICB治疗的非小细胞肺癌（NSCLC）中的临床意义仍不清楚。从公开可获取的数据中检索了接受抗PD-1/PD-L1或抗CTLA-4抗体治疗的NSCLC患者的基因组和生存数据（Rizvi2015；Hellmann2018；Rizvi2018；Samstein2019）。1007例NSCLC患者的基因组、生存和mRNA数据来自癌症基因组图谱（TCGA）。在三个独立的Rizvi2015、Hellmann2018和Rizvi2018队列中， 突变与更好的无进展生存期（PFS）显著相关。 突变型NSCLC患者的中位PFS未达到，野生型NSCLC患者的中位PFS为6.3个月（Rizvi2015，HR = 0.16；95%CI，0.02 - 1.17；P = 0.03）、24.0个月对5.4个月（Hellmann2018，HR，0.49；95%CI，0.26 - 0.94；P = 0.03）、5.6个月对3.0个月（Rizvi2018，HR = 0.64；95%CI，0.44 - 0.92；P = 0.01）以及6.8个月对3.5个月（合并队列，HR，0.54；95%CI，0.39 - 0.73；P < 0.0001）。在合并队列中， 突变是PFS的独立预测因素（P = 0.01）。此外，在Samstein2019队列中， 突变与更好的总生存期（OS）相关（19个月对10个月，P = 0.03）。而在未接受ICB治疗的患者中未观察到类似的临床获益（TCGA队列，P = 0.78）。在进一步的探索性分析中， 突变与肿瘤突变负担增加以及JAK1和STAT1的mRNA表达升高显著相关。基因集富集分析显示，在有 突变的患者中，与抗原加工和呈递相关的特征显著富集。这项研究表明， 突变可能是NSCLC中ICB的潜在阳性预测指标。这些结果需要在未来进一步证实。
