title: GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cellsin vitro.
abstract: Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune-targeted treatment by promoting an immune-suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid-derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes. Pancreatic cancer in particular supports MDSC differentiation via the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), and MDSC are believed to contribute to the profoundly immune-suppressive microenvironment present in pancreatic tumours. MDSC-targeted therapies that deplete or inhibit this cell population have been proposed as a way to shift the balance in favour of a tumour-clearing immune response. In this study, we have modelled MDSC differentiation and functionin vitroand this has provided us with the opportunity to test a range of potential MDSC-targeted therapies to identify candidates for further investigation. Usingin vitromodelling we show here that the combination of GM-CSF-signalling blockade and gemcitabine suppresses both the MDSC phenotype and the inhibition of T-cell function by MDSC.
authors.affiliation: Translational Oncology, Centre for Cancer Biology, SA Pathology and the University of South Australia , Adelaide, Australia.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gargett
authors.affiliation: Translational Oncology, Centre for Cancer Biology, SA Pathology and the University of South Australia , Adelaide, Australia.
authors.forename: Susan N
authors.initials: SN
authors.lastname: Christo
authors.affiliation: Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia , Adelaide, Australia.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hercus
authors.affiliation: Cancer Clinical Trials Unit, Royal Adelaide Hospital , Adelaide, Australia.
authors.forename: Nazim
authors.initials: N
authors.lastname: Abbas
authors.affiliation: Cancer Clinical Trials Unit, Royal Adelaide Hospital , Adelaide, Australia.
authors.forename: Nimit
authors.initials: N
authors.lastname: Singhal
authors.affiliation: Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia , Adelaide, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Translational Oncology, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia; Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia; Discipline of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown