The role of tumor-derived exosomes in the formation of a pre-metastatic niche in cancer

Abstract

Abstract Purpose Determine if tumor derived exosomes (TDE) can drive cancer progression through polarization of immunosuppressive cell phenotypes capable of restricting αβ T cell functioning. Preliminary data shows that exosome stimulation differentially upregulates PD-L1 (programmed-death-ligand-1) expression on peritoneal macrophages and lung resident γδ T cells while also upregulating PD-1 expression on αβ T cells. The ultimate goal is to assess whether elimination of TDE can synergize with current PD-1/PD-L1 treatments by removing antagonizing factors and improving clinical outcomes. Methods TDE were isolated using serial ultracentrifugation from Lewis Lung Carcinoma cells. Exosome stimulated peritoneal macrophages and γδ T cells were co-cultured with ova-transgenic –I (CD8+) T-cells to assay for suppressive function. Anti-PD-1 antibody was added to the culture to confirm that the PD-1/PDL-1 axis mediates the immune suppression. The effect of TDE on γδ T cell metabolism was also investigated. Lastly, human peripheral blood samples from lung cancer and anti-PD-1 treated lung cancer patients were compared via flow cytometry for γδ/PD-L1 expression profiling. Results The results suggest that TDE play a role in tumor metastasis by polarizing γδ T cells and macrophages to an immunosuppressive PD-L1+ phenotype capable of restricting αβ T cell effector functioning. Discussion/Conclusion TDE could be directly antagonizing the effects of immune checkpoint therapies. Therefore, future experiments will focus on eliminating exosome secretion by using siRNARab27 inhibition and the small drug compound, cambinol, concurrently with anti-PD-1 or anti-PD-L1 monoclonal antibody in efforts to increase progression free survival.