Abstract 3746: Dynamic characterization of small RNAs in non small cell lung cancer exosomes under immune-checkpoint inhibitor treatments
Authors: Garrido-Barros Maria , Oliver Javier , Onieva Juan Luis , Martinez-Galvez Beatriz , Duddelman Jaime , Rueda Antonio , Perez Elisabeth , Alba Emilio , Ramos Inmaculada , Zafra Juan , Cobo Manuel , Barragán Isabel 
Published: April 2023

Abstract
Immunotherapy based on Immune Checkpoint blockade (ICB) has become a significant therapeutic option for advanced Non Small Cell Lung Cancer (NSCLC) patients. However, there is an urgent need to find novel biomarkers that to reliably stratify good responders to immunotherapy. Currently, the available biomarkers are not specific enough. Exosomes are small membrane vesicles with sizes of 30-100 nm secreted by most cell types including cancer cells. Exosomes operate as an intercellular communication system by sending proteins, mRNA and miRNAs among other relevant RNA molecules. Exosomes enriched with miRNAS are involved in proliferation, differentiation, maduration and immune cell activation. Moreover, in cancer cells miRNA and other small RNA molecule expressions are dysregulated. Exosomes produced from cancer patient's plasma have been shown to be accurate diagnostic tools for the disease. In this study we profiled miRNAs and other small RNA cargo by exosome of plasma samples from 77 Non Small Cell Lung Cancer (NSCLC) metastatic patients before and after the first cycle of immunotherapy to evaluate the potentiality of predicting response to immunotherapy. We perform exosomes together with RNA isolation and small RNAseq sequencing from plasma samples before and after the first ICB cycle. Two independent softwares were used to identify small RNAs (RNAtoolbox and mirMaster). Prior ICB treatment we did not find differentially expressed miRNAs or other small RNA between good and bad responders. Interestingly we identified 12 exosomal miRNA differentially expressed between good and bad responders after the first cycle of ICB. Intriguingly, levels of miR-134-5p, miR-142-3p, miR-143-3p among others previously associated with NSCLC were found to be considerably higher in the good responder group than the bad responder group. Regarding other smallRNA molecules we observed a great variety and variability of piRNA, rRNA, scaRNA, lncRNA, snoRNA, snRNA, miscRNA and circRNA. To address the function of miRNA and other differentially expressed RNA molecules, we consulted KEGG, GO and Reactome for gene regulatory networks. Interestingly, KEGG results show pathways in cancer as top hit and Reactome highlight Immune System and cancer hits. In conclusion, we observed that patients that have favorable response to ICB have distinctive plasma exosomal miRNA patterns that could be used as possible biomarkers for predicting the effectiveness of immunotherapy in advanced NSCLC patients
Citation Format: Maria Garrido-Barros, Javier Oliver, Juan Luis Onieva, Beatriz Martinez-Galvez, Jaime Duddelman, Antonio Rueda, Elisabeth Perez, Emilio Alba, Inmaculada Ramos, Juan Zafra, Manuel Cobo, Isabel Barragán. Dynamic characterization of small RNAs in non small cell lung cancer exosomes under immune-checkpoint inhibitor treatments. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3746.