Immune-Cell-Derived Exosomes as a Potential Novel Tool to Investigate Immune Responsiveness in SCLC Patients: A Proof-of-Concept Study.

Simple Summary: In the era of precision medicine and immunotherapy, the isolation and characterization of exosomes from the peripheral blood mononuclear cells (PBMC-EXs) of SCLC patients may represent a new tool to define responder (BR) from non-responder (NR) patients undergoing chemoimmunotherapy treatment. In this proof-of-concept study, we isolated PBMC-EXs from the peripheral blood of SCLC patients and investigated the potential role of such extracellular vesicles (EVs) in monitoring tumor response to drug stimuli. Interestingly, we found increased exosome levels of c-Myc and Snail along with reduced levels of the immune markers MAVS and STING in NR patients. Also, we showed that PBMC-EXs from BR patients induced an increase in apoptosis and a reduction in the cell viability of SCLC cells compared to PBMC-EXs from NR SCLC patients. Thus, we suggest that PBMC-EXs may represent an innovative strategy to be further explored for the therapy and selection of immune-responsive SCLC patients. Small cell lung cancer (SCLC) is a highly invasive and rapidly proliferating lung tumor subtype. Most patients respond well to a combination of platinum-based chemotherapy and PD-1/PDL-1 inhibitors. Unfortunately, not all patients benefit from this treatment regimen, and few alternative therapies are available. In this scenario, the identification of new biomarkers and differential therapeutic strategies to improve tumor response becomes urgent. Here, we investigated the role of exosomes (EXs) released from the peripheral blood mononuclear cells (PBMCs) of SCLC patients in mediating the functional crosstalk between the immune system and tumors in response to treatments. In this study, we showed that PBMC-EXs from SCLC patients with different responses to chemoimmunotherapy showed different levels of immune (STING and MAVS) and EMT (Snail and c-Myc) markers. We demonstrated that PBMC-EXs derived from best responder (BR) patients were able to induce a significant increase in apoptosis in SCLC cell lines in vitro compared to PBMC-EXs derived from non-responder (NR) SCLC patients. PBMC-EXs were able to affect cell viability and modulate apoptotic markers, DNA damage and the replication stress pathway, as well as the occurrence of EMT. Our work provides proof of concept that PBMC-EXs can be used as a tool to study the crosstalk between cancer cells and immune cells and that PBMC-EXs exhibit an in vitro ability to promote cancer cell death and reduce tumor aggressiveness. [ABSTRACT FROM AUTHOR]