Noninvasive monitoring of therapeutic response to immune checkpoint inhibitors using circulating exosomes in non-small cell lung cancer

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Summary/ Abstract: The emergence of immune checkpoint blockade (ICB) therapy has revolutionized the treatment for advanced cancers including lung cancer. Particularly, anti-PD-1/PD-L1 therapy shows promising therapeutic outcomes, and some of these therapies are employed as the first line treatment of patients with metastatic NSCLC. However, not all patients benefit from ICB and some of patients who initially respond to ICB develop acquired resistance and sometimes. multisystem immune-related adverse events. Thus, it is critically important to accurately identify and predict lung cancer patients who will respond to ICB before and during a course of treatment. Here, we propose an innovative screening strategy aiming at early prediction and real-time monitoring of responders and non-responders to ICB for lung cancer patients. This approach is based on the isolation, detection, and characterization of circulating exosomes specifically associated with anticancer immune response rather than analyzing total pool of exosomes. Exosomes are secreted nano-sized particles containing nucleic acid, protein, and lipid cargo specific to the cell of origin, which are considered as a mirror of the parental cells. Besides, they can be easily extracted from biofluids as a source of biomarkers of disease status and treatment response. Herein, we seek to specifically analyze two population of circulating exosomes including tumor-derived exosomes (TEXs) and PD-L1+ exosomes that serve as the invaluable determinants of the status of tumor burden and anticancer-immune activity, respectively. We have formulated two Specific Aims that hinge on developing technologies to achieve our goals: Aim1 will develop a highly sensitive and selective sensing platform for quantitative analysis of TEXs and PD-L1+ exosomes followed by molecular analysis of TEXs to explore the molecular signatures associated with treatment outcome. For that, we will genetically engineer novel bioluminescence-based probes by fusing bioluminescence proteins with tumor-specific and PD-L1-specific targeting molecules, respectively. Aim 2 will evaluate circulating exosomes from serum of NSCLC patients treated with ICB therapy. The platform developed in Aim 1 will be used for the quantitative analysis of TEXs and PD-L1+ exosomes during the treatment, and whether the observed changes can be utilized as a predictive marker for early identification and monitoring of responders and non-responders to ICB. The circulating TEXs will be subsequently isolated; their exosomal transcripts, and long non-coding RNAs will be characterized by using next-generation sequencing to explore the molecular signatures associated with therapeutic outcome. We will apply computational approaches for data integration, analysis, and interpretation based on the number of TEXs, expression level of exosomal PD-L1, molecular signatures of TEXs, and patient’s clinical features. In sum, our project is highly translational and could have a significant impact on lung cancer patients. If successful, this research will help physicians to accurately predict and identify patients who will benefit from ICB therapy, and develop potential novel treatments for patients who are non-responders to ICB therapy.