Abstract
Malignant pleural effusion (MPE) is a frequent clinical problem which remains incurable. There is still an unmet need for developing MPE treatments to improve clinical outcomes as current management remedies are mostly palliative for symptom alleviation. Chemotherapeutic drugs on top of their direct cytotoxicity could invigorate anti-tumour immunity and reduce the immunosuppressive MPE microenvironment.
To evaluate the immunogenic effect of chemotherapies, 3 MPE derived cell lines (MPE174, MPE278 and MPE392) were treated with seven FDA-approved chemotherapeutic drugs. Flow cytometry examination showed that MHC I was upregulated at various levels by dactinomycin, dinaciclib and bortezomib. Mass spectrometry analysis comparing cells pre and post treatment suggested that stimulator of interferon genes (STING) and IFN-stimulated genes (ISGs) were upregulated by dactinomycin. Moreover, MHC I antigen processing and presentation pathway and type I interferon (IFN) signalling of cancer cells were detected altered after dactinomycin treatment with STRING enrichment and gene ontology analysis. Cell viability assay showed cytotoxicity of dactinomycin could be partly reversed by STING inhibitor, JAK inhibitor and TBK-1 inhibitor. Following dactinomycin treatment, the cancer cells were co-cultured with SSX-2-specific CD8+ T lymphocytes or allogenic NK cells. We found that both killing capacity of CD8+ T cells and NK cells were enhanced by dactinomycin.
In summary, our data suggest that dactinomycin could benefit CD8+ T and NK lymphocytes mediated immune response through STING pathway and MHC I regulation.