Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy
Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy
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DOI：
10.1007/s00262-021-03106-z
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发表时间：
2021-11
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通讯作者：
Q. Tan;L. Dai;Yan-rong Wang;Shuxia Liu;T. Liang;R. Luo;Shasha Wang;N. Lou;Haizhu Chen;Yu Zhou;Q. Zhong;Jian-liang Yang;P. Xing;Xingsheng Hu;Yutao Liu;Shengyu Zhou;Jiarui Yao;Di Wu;Zhishang Zhang;Le Tang;Xiaobo Yu;Xiaohong Han;Yuankai Shi
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作者：
Q. Tan;L. Dai;Yan-rong Wang;Shuxia Liu;T. Liang;R. Luo;Shasha Wang;N. Lou;Haizhu Chen;Yu Zhou;Q. Zhong;Jian-liang Yang;P. Xing;Xingsheng Hu;Yutao Liu;Shengyu Zhou;Jiarui Yao;Di Wu;Zhishang Zhang;Le Tang;Xiaobo Yu;Xiaohong Han;Yuankai Shi
背景针对程序性细胞死亡-1(PD1)及其配体(PDL1)的抗体已经使癌症治疗发生了革命性的变化。然而，抗PD1/PDL1自身抗体(AABS)在多种癌症类型中的分布及其在抗PD1治疗中的潜在生物标志物作用尚不清楚。方法采用酶联免疫吸附试验(EL ISA)检测190例肺癌、乳腺癌、食道癌、结直肠癌、肝癌、前列腺癌、宫颈癌、卵巢癌、胃癌、淋巴瘤等10种癌症患者血浆中抗PD1/PDL1自身抗体(AABS)及其亚类(IgG1-4)，分析AABS与多种临床参数的综合相关性。我们在76例接受抗PD1治疗的非小细胞肺癌标本中进一步检测了这些抗体，并在一个独立的队列(n= 32)中分析和验证了这些抗体水平与生存的关系。抗PD1/PDL1AABS的主要亚型为IgG1和IgG2。相关分析揭示了不同癌症类型之间的不同图景。随机森林模型显示，IgG4亚型主要与癌症有关。在76例非小细胞肺癌患者的发现队列中，高抗PD1IgG4与总生存期减少(OS，p= 0.019)有关，而与无进展生存期(pFS，p= 0.088)无关。在32例非小细胞肺癌患者中，抗PD1IgG4抗体与OS呈负相关(p= 0.032)。结论本研究首次报道了10种肿瘤类型中抗PD1IgG4抗体及其亚类的分布。此外，抗PD1 AAB IgG4亚类与OS相关，可能成为非小细胞肺癌患者抗PD1治疗生存受益的潜在生物标志物。
BackgroundAntibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy.MethodPlasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n= 32).ResultsAnti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS,p= 0.019), not progression-free survival (PFS,p= 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p= 0.032).ConclusionThis study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.