Abstract
Simple SummaryPurpose of this study was to investigate the prognostic and predictive role of blood circulating extracellular vesicles (EVs) in patients with advanced non-small cell lung cancer treated with immunotherapy. A newly optimized flow cytometry protocol was applied for identification and subtyping of blood circulating EVs in a total cohort of 59 NSCLC patients, which included 31 patients treated with anti-PD-1/PD-L1 agents and 28 patients treated with traditional chemotherapy. Our results show that pre-treatment concentration of blood circulating endothelial-derived EVs was correlated with overall survival and clinical response in patients treated with immunotherapy. Additionally, proteomic analysis of purified blood circulating EVs indicated differences in EV protein cargo between responders and non-responders to immunotherapy. These findings may pave the way to the identification of novel immunotherapy biomarkers in patients with advanced NSCLC.Immune checkpoint inhibitors (ICIs) induce durable clinical responses only in a subset of advanced non-small cell lung cancer (NSCLC) patients. There is a need to identify mechanisms of ICI resistance and immunotherapy biomarkers to improve clinical benefit. In this study, we evaluated the prognostic and predictive value of circulating endothelial and leukocyte-derived extracellular vesicles (EV) in patients with advanced NSCLC treated with anti-PD-1/PD-L1 agents. In addition, the relationship between total blood circulating EV proteome and response to ICIs was investigated. An optimized flow cytometry method was employed for the identification and subtyping of blood circulating EVs in 59 patients with advanced NSCLC. Blood samples were collected from patients receiving anti-PD-1/PD-L1 inhibitors (n = 31) or chemotherapy (n = 28). An exploratory proteomic analysis of sorted blood EVs was conducted in a subset of patients. Our results show that a low blood concentration of circulating endothelial-derived EVs before treatment was strongly associated to longer overall survival (p = 0.0004) and higher disease control rate (p = 0.045) in patients treated with ICIs. Interestingly, shotgun proteomics revealed that EVs of responders to anti-PD-1 therapy had a specific protein cargo before treatment. In addition, EV protein cargo was specifically modulated during immunotherapy. We identified a previously unknown association between circulating endothelial-derived extracellular vesicle concentration and immunotherapy-related clinical outcomes. We also observed differences in circulating extracellular vesicle proteome according to anti-PD-1-based treatment response in NSCLC patients. Overall, these results may contribute to the identification of novel circulating biomarkers for rational immunotherapy approaches in patients affected by NSCLC.
Highlights
A growing understanding of cancer immune escape mechanisms led to the development and application of promising novel immunotherapy agents in non-small cell lung cancer (NSCLC) [1]
A total of 31 patients were treated with PD-1 or PD-L1 inhibitor monotherapy
One-year overall survival (OS) was 39% for the overall population, 48% for patients treated with Immune checkpoint inhibitors (ICIs) and 30% for the chemotherapy group
Summary
A growing understanding of cancer immune escape mechanisms led to the development and application of promising novel immunotherapy agents in NSCLC [1] Despite advances in this field, a subgroup of patients bears tumors, which fail to respond or acquire resistance to the immunotherapeutic strategy [2]. There is a growing need for biomarkers that will enhance patient selection and understanding of immunotherapy response, helping to improve and personalize treatment regimens [3] In this regard, obtaining tissue-related biomarkers is often challenging in advanced disease and expression of such biomarkers (e.g., cancer programmed cell death-ligand 1, PD-L1) display variability in time and space within the tumor, limiting their predictive value [4].
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