7O - Peripheral blood-derived immune cells as tools to identify novel immunotherapy biomarkers in SCLC

Background

Small cell lung cancer (SCLC) is currently treated with a combination of chemo- and immunotherapy. Unfortunately, not all patients benefit from this treatment regimen and few alternative therapies are available. In this scenario, predictive biomarkers to identify high-risk patients are still needed. Here, we explored the role of peripheral blood mononuclear cells (PBMCs) and PBMC-derived exosomes (PBMC-Ex) as a tool for novel biomarkers searching.

Methods

SCLC patients enrolled (n=25) were divided into best responders (BR), responders (R) and non-responders (NR). PBMCs from SCLC patients (n=10) were subjected to whole exome sequencing (WES) and RNA-seq. Isolation and characterization of PBMC-Ex from BR and NR cohorts were performed.

Results

PBMCs from BR and R patients of SCLC cohorts showed the highest levels of STING (p < 0.0001), a key cytosolic DNA sensor, and CXCL10 (p < 0.0001), a STING downstream innate immune pathway activation marker. The mRNA expression levels of STING, cGAS, CXCL10 and CCL5 in such blood cells were significantly lower (p < 0.0005) in the NR cohort as compared to BR. From WES germline genetic testing, we identified heterozygous germline LoF variants in DDR genes (POLE, POLD1, RAD51B, CHEK1, ATM) in BR and R SCLC patients, whereas no germline variants in the DDR genes panel were found in the NR cohort. This trend, if later validated in a larger cohort of patients, may suggest that deleterious DDR variants in the PBMCs of patients might impact the response to immunotherapy. GSEA analysis of RNAseq data further confirmed an increase in STING-related innate immune activity as well as IFN-related pathways enrichment in BR patients derived PBMC in comparison to NR patients. PBMC-EXs from SCLC patients with different responses to chemo-immunotherapy showed different levels of immune (STING and MAVS) and EMT (SNAIL and c-Myc) markers. PBMC-EXs derived from BR patients were able to induce a significant increase of apoptosis in SCLC cell lines in vitro compared to PBMC-EXs derived from NR patients.

Conclusions

cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

AIRC, Fondazione Italiana per la Ricerca sul Cancro.

Disclosure

All authors have declared no conflicts of interest.