Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, Beijing, 100021, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, 102206, China.
Cancer Immunol Immunother. 2022 Jul;71(7):1681-1691. doi: 10.1007/s00262-021-03106-z. Epub 2021 Nov 24.
Antibodies 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.
Plasma 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).
Anti-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).
This 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.
针对程序性细胞死亡蛋白 1（PD1）及其配体（PDL1）的抗体已经彻底改变了癌症治疗。然而，人们对多种癌症中预先存在的抗 PD1/PDL1 自身抗体（AAbs）的分布知之甚少，也不知道它们对抗 PD1 治疗的潜在生物标志物作用。
通过酶联免疫吸附试验（ELISA）检测了 190 名癌症患者（涵盖 10 种癌症类型：肺癌、乳腺癌、食管癌、结直肠癌、肝癌、前列腺癌、宫颈癌、卵巢癌、胃癌和淋巴瘤）的血浆抗 PD1/PDL1 AAb IgG 和亚类（IgG1-4），分析了 AAbs 与多种临床参数的综合相关性。我们进一步在 76 名接受抗 PD1 治疗的非小细胞肺癌（NSCLC）样本中测试了这些 AAbs，分析并验证了 AAbs 水平与生存的相关性，该验证在一个独立队列（n=32）中进行。
在 10 种癌症患者中均检测到抗 PD1/PDL1 AAb IgG。抗 PD1/PDL1 AAbs 的主要亚型为 IgG1 和 IgG2。相关性分析显示，不同癌症类型之间存在明显的差异。随机森林模型表明，IgG4 亚类与癌症的关系最为密切。在 76 名 NSCLC 患者的发现队列中，高抗 PD1 IgG4 与总生存期（OS，p=0.019）而非无进展生存期（PFS，p=0.088）降低相关。在 32 名 NSCLC 患者中验证了抗 PD1 IgG4 与 OS 的负相关（p=0.032）。
本研究首次报告了预先存在的抗 PD1/PDL1 AAb IgG 和亚类在 10 种癌症中的分布情况。此外，鉴定出抗 PD1 AAb IgG4 亚类与 OS 相关，这可能成为 NSCLC 患者抗 PD1 治疗生存获益的潜在生物标志物。
