Abstract 411P
Background
Despite the development of immune checkpoint inhibitors therapy (ICI) in non-small cell lung cancer (NSCLC) patients, most of them eventually experience relapse. Small extracellular vesicles (sEV) are currently emerging as promising biomarkers. They are released by all cell types, participate at the cell-cell communication and can be found in all body fluids, reflecting at distance the state of the tumor. Here, we investigated i) the immunosuppressive role of sEV derived frompatient’s NSCLC (NSCLC-sEV) on antitumoral CD8+ T cells and ii) their use as biomarkers of response to ICI in the BREATHE (Biocollection for REseArch in THoracic cancer) biocollection.
Methods
NSCLC-sEV were purified by ultracentrifugation from NSCLC patient-derived cell lines, from tumor resection or from plasma (ethics agreement DC-2011-1399, DC-2017-2987). Their immunosuppressive effects were studied by exposing CD8+ T cells to NSCLC-sEV, where their activation, proliferation, and viability were assessed. Their use as biomarker was investigating by NGS sequencing of their miRNA cargo.
Results
CD8+ T cells exposed to NSCLC-sEV showed reduced expression of their activation markers CD25 and CD45, and decreased secretion of antitumoral TNFα, granzyme B, and perforin-1, suggesting that they are unable to conduct an efficient anti-tumoral response. NSCLC-sEV also upregulated the CD8+ immune checkpoint markers, such as PD-1, TIGIT, and TIM-3, and decreased the viability and proliferation of exposed CD8+ T cells. These effects seem mediated by miRNAs included into sEV. NSCLC-sEV and their miRNA cargo, at diagnosis, are also promising biomarkers of response to ICI since we identified 17 miRNAs which discriminate efficiently non-responders (patient having a disease progression by RECIST criteria on first CT evaluation) and long-term responders (patients free-from-progression at 18 months after the beginning of treatment).
Conclusions
MiRNAs included into sEV derived from tumor cells can impair CD8+ T cell response against cancer and are promising biomarkers of response to immunotherapy in NSCLC.
Clinical trial identification
NCT06481813.
Legal entity responsible for the study
E. Pons-Tostivint.
Funding
INSERM, fondation ARC, Ligue contre le cancer.
Disclosure
All authors have declared no conflicts of interest.