EXOSOMES AS PREDICTIVE BIOMARKERS OF CLINICAL RESPONSE TO IMMUNE CHECKPOINT INHIBITOR (ICI) THERAPY IN NON-SMALL CELL LUNG CANCER (NSCLC)

Abstract

ABSTRACT Lung cancer is the leading cause of cancer-related mortality worldwide. In the era of precision medicine, the need to validate non-invasive predictive biomarkers in clinical practice is still a significant challenge. Further, given the fact that tumor is extremely heterogeneous, reliance on a single biomarker to predict the efficacy of immunotherapy may be difficult. We conducted a comprehensive study to evaluate the usefulness of serum-derived exosomal immuno-oncological proteins and cytokines in NSCLC patients to serve as surrogate markers in monitoring treatment response and allowing stratification of patients for maximum therapeutic benefit. We found the baseline concentrations of most immuno-oncology proteins were significantly higher in exosomes compared to their soluble free forms in the serum of NSCLC patients. We compared the expression of exoPD-L1 with tissue PD-L1 and our results showed that exoPD-L1 was present in all the patients (100%), while only 71% of patients were tissue PD-L1 positive, indicating that exoPD-L1 is more reliable marker. Further, we assessed the change in expressional levels of exosomal immuno-oncological proteins and cytokines and their correlation with tumor response to ICI treatment. Our findings showed that post-treatment, the considerable downregulation of exosomal PD-L1, E-Cadherin, ULBP1, ULBP3, MICA, MICB, Siglec7 and significant upregulation of exosomal PD-1 and IFN-Gamma, was associated with tumor regression. Further, the significant increase of exoPD-L1 was correlated with disease progression. Additionally, we reported preferential expression of CD91 in NSCLC patient’s exosomes compared to healthy controls and confirmed its localization on the exosomal surface, suggesting exosomal CD91 as a potential biomarker for NSCLC. Overall, our findings demonstrate that exosomal immuno-oncological proteins and cytokines may be useful in monitoring patient response to ICI treatment and clinical outcomes in NSCLC.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences