Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma.
Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma.
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DOI：
10.1136/jitc-2022-006552
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发表时间：
2023-08
影响因子：
10.9
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中科院分区：
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基于免疫检查点抑制剂（ICI）的治疗已被推荐为难治性复发和/或转移性鼻咽癌（NPC）患者的一线治疗，但反应各不相同，迫切需要预测性生物标志物。我们从四种白细胞介素中筛选出血清白细胞介素15（sIL-15）作为候选生物标志物，而大多数鼻咽癌患者的sIL-15水平较低，常规方法无法检测，因此有必要建立一种高灵敏度的检测方法，以筛选出对ICIs治疗获益最大或最小的鼻咽癌患者。结合引物交换反应（PER），转录介导的扩增（TMA）和免疫PER-TMA-CRISPR/Cas 13 a系统，我们开发了一种新的多重信号扩增平台，检测限为32 fg/mL，比ELISA灵敏153倍。该平台具有高度的特异性、可重复性和通用性。当应用于130份NPC血清的两个独立队列时，sIL-15的预测值在两个队列中均准确（曲线下面积：训练，0.882;验证，0.898）。此外，较低的sIL-15水平与较差的无进展生存期相关（训练，HR：0.080，p<0.0001;验证，HR：0.053，p<0.0001）。本工作提出了一种简单、灵敏的检测sIL-15的方法，为鼻咽癌患者的个性化免疫治疗提供了依据。
Immune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed. We selected serum interleukin-15 (sIL-15) out of four interleukins as a candidate biomarker, while most patients’ sIL-15 levels were too low to be detected by conventional methods, so it was necessary to construct a highly sensitive method to detect sIL-15 in order to select NPC patients who would benefit most or least from ICIs. Combining a primer exchange reaction (PER), transcription-mediated amplification (TMA), and a immuno-PER-TMA-CRISPR/Cas13a system, we developed a novel multiple signal amplification platform with a detection limit of 32 fg/mL, making it 153-fold more sensitive than ELISA. This platform demonstrated high specificity, repeatability, and versatility. When applied to two independent cohorts of 130 NPC sera, the predictive value of sIL-15 was accurate in both cohorts (area under the curve: training, 0.882; validation, 0.898). Additionally, lower sIL-15 levels were correlated with poorer progression-free survival (training, HR: 0.080, p<0.0001; validation, HR: 0.053, p<0.0001). This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.
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