73P - Effect of combination therapy with atezolizumab plus metformin on peripheral immune cells from NSCLC patients

Background

Although immunotherapy (IO) offers significant advances in the clinical management of NonSmall Cell Lung Cancer (NSCLC), durable benefits are not achieved in all patients. Mechanisms of resistance to IO in NSCLC are complex, mainly comprising tumor and infiltrating immune cells. However, resistance landscape against PD-1 blockade remains unclear. More recently, some evidence has provided evidence for metformin overcoming primary resistance to PD-1 inhibitor in mutant NSCLC models. Considering this, we aimed to assess the impact of the combined treatment of metformin plus atezolizumab on antitumor immune response from NSCLC patients-derived peripheral blood immune cells (PBMCs).

Methods

mRNA and protein expression of cGAS-STING downstream pathway and monocyte M1 marker levels were measured in PBMCs from NSCLC patients. MTS assay was used to assess cell viability of NSCLC cell lines co-cultured with PBMCs or monocyte-conditioned medium. Evaluation of senescence phenotype was also performed based on a histochemical stain for the detection of β-galactosidase activity. Colony-forming ability of NSCLC cell lines co-cultured with immune cells derived from NSCLC patients (pre-treated with metformin 2 mM + atezolizumab 10 μg/ml for 48h) was also assessed.

Results

Metformin ± atezolizumab was able to activate the cGAS-STING pathway in PBMC-derived lymphocytes from NSCLC patients and reduce in vitro cell viability of NSCLC cells in 2D co-culture. Colony formation ability of NSCLC cell lines was reduced by activated lymphocytes pre-treated with metformin ± atezolizumab. Evaluation of the senescent phenotype in PBMC-isolated monocytes showed the greatest reduction in blue staining in the presence of the combined treatments. We also observed a reduction in cell viability by MTS assay of NSCLC cells cultured with monocyte-conditioned media treated with metformin ± atezolizumab. Furthermore, we found increased levels of M1 markers (TNFα, IL1β) in monocytes treated with the combined therapy.

Conclusions

Our results provide a novel role for synergistic effects of metformin combined with IO in enhancing the anti-tumor activity of multiple immune cells subsets from NSCLC patients.

Editorial acknowledgement

NA

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.