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Abstract：
Chemoimmunotherapy has evolved as a standard treatment for advanced non-small cell lung cancer (aNSCLC). However, inevitable drug resistance has limited its efficacy, highlighting the urgent need for biomarkers of chemoimmunotherapy. A three-phase strategy to discover, verify, and validate longitudinal predictive autoantibodies (AAbs) for aNSCLC before and after chemoimmunotherapy was employed. A total of 528 plasma samples from 267 aNSCLC patients before and after anti-PD1 immunotherapy were collected, plus 30 independent formalin-fixed paraffin-embedded samples. Candidate AAbs were firstly selected using a HuProt high-density microarray containing 21,000 proteins in the discovery phase, followed by validation using an aNSCLC-focused microarray. Longitudinal predictive AAbs were chosen for ELISA based on responders versus non-responders comparison and progression-free survival (PFS) survival analysis. Prognostic markers were also validated using immunohistochemistry and publicly available immunotherapy datasets. We identified and validated a panel of two AAbs (MAX and DHX29) as pre-treatment biomarkers and another panel of two AAbs (MAX and TAPBP) as on-treatment predictive markers in aNSCLC patients undergoing chemoimmunotherapy. All three AAbs exhibited a positive correlation with early responses and PFS (p < 0.05). The kinetics of MAX AAb showed an increasing trend in responders (p < 0.05) and a tendency to initially increase and then decrease in non-responders (p < 0.05). Importantly, MAX protein and mRNA levels effectively discriminated PFS (p < 0.05) in aNSCLC patients treated with immunotherapy. Our results present a longitudinal analysis of changes in prognostic AAbs in aNSCLC patients undergoing chemoimmunotherapy.
摘要：
化学免疫疗法已发展成为晚期非小细胞肺癌（aNSCLC）的标准治疗方法。然而,不可避免的耐药性限制了其疗效，强调迫切需要化学免疫疗法的生物标志物。一个三阶段的战略来发现，验证,并验证在使用化学免疫疗法前后aNSCLC的纵向预测性自身抗体（AAbs）。共收集了267例抗PD1免疫治疗前后aNSCLC患者的528份血浆样本，加上30个独立的福尔马林固定石蜡包埋样品。在发现阶段，首先使用含有21,000种蛋白质的HuProtTM高密度微阵列选择候选AAb，然后使用aNSCLC聚焦微阵列进行验证。基于应答者与非应答者的比较和无进展存活(PFS)存活分析,选择纵向预测性AAbs用于酶联免疫吸附测定(ELISA)。还使用免疫组织化学和公开可用的免疫疗法数据集验证了预后标志物。我们在接受化学免疫疗法的aNSCLC患者中鉴定并验证了一组两种AAbs（MAX和DHX29）作为治疗前生物标志物，另一组两种AAbs（MAX和TAPBP）作为治疗中的预测标志物。所有三种AAbs均与早期反应和PFS呈正相关(p<0.05)。MAXAAb的动力学在响应者中显示出增加的趋势（p<0.05），在非响应者中显示出最初增加然后减少的趋势（p<0.05）。重要的是,MAX蛋白和mRNA水平可有效区分接受免疫治疗的aNSCLC患者的PFS（p<0.05）。我们的结果提供了接受化学免疫治疗的aNSCLC患者预后AAbs变化的纵向分析。
