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Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic
Ya-Xian Wu1, Shan Xing1, Yu Wang2
1Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
Background:
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.
Methods:
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.
Results:
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).
Conclusion:
This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.
Insights
A new highly sensitive method detects low serum interleukin-15 (sIL-15) levels in nasopharyngeal carcinoma (NPC) patients. This biomarker predicts response to immune checkpoint inhibitors (ICIs), aiding personalized immunotherapy decisions.
Area of Science:
- Biomarker Discovery
- Molecular Diagnostics
- Cancer Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) are first-line treatments for advanced nasopharyngeal carcinoma (NPC), but patient responses vary significantly.
- Predictive biomarkers are crucial for identifying NPC patients most likely to benefit from ICIs.
- Serum interleukin-15 (sIL-15) is a potential biomarker, but its low levels in most patients necessitate a highly sensitive detection method.
Purpose of the Study:
- To develop a novel, highly sensitive detection platform for serum interleukin-15 (sIL-15).
- To evaluate the predictive value of sIL-15 for immune checkpoint inhibitor (ICI) therapy response in nasopharyngeal carcinoma (NPC) patients.
- To establish sIL-15 as a biomarker for personalized immunotherapy in NPC.
Main Methods:
- Developed a novel multiple signal amplification platform combining primer exchange reaction (PER), transcription-mediated amplification (TMA), and CRISPR/Cas13a.
- Achieved a detection limit of 32 fg/mL for sIL-15, representing a 153-fold increase in sensitivity compared to ELISA.
- Validated the platform's specificity, repeatability, and versatility in detecting sIL-15.
Main Results:
- The developed platform accurately predicted ICI response in two independent NPC patient cohorts (AUC: 0.882 training, 0.898 validation).
- Lower sIL-15 levels were significantly correlated with poorer progression-free survival in both training and validation cohorts (HR < 0.080, p < 0.0001).
- The method demonstrated high accuracy and reliability for sIL-15 quantification in NPC sera.
Conclusions:
- A simple and highly sensitive method for sIL-15 detection was successfully developed.
- Serum IL-15 serves as a valuable predictive biomarker for ICI therapy in NPC patients.
- This approach offers insights for guiding personalized immunotherapy strategies in NPC.
