GM‐CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid‐derived suppressor cells in 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 function in vitro and this has provided us with the opportunity to test a range of potential MDSC-targeted therapies to identify candidates for further investigation. Using in vitro modelling 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.

Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression

“…19,20 In addition, GM-CSF blockade was able to abolish the immunosuppressive features of human MDSCs in vitro, highlighting GM-CSF as one of the main regulators of MDSC expansion. 21…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…Recent studies have reported that in the animal model of endometriosis, chemokines CCL1/2/5 promote the migration of CXCR2 + MDSC to heterotopic grafts, performing immunosuppressive function . GM‐CSF is an important one released by tumor cells, which can promote the proliferation of MDSCs, while G‐CSF can affect the migration of MDSCs probably by upregulating the expression of Bv8, a surface protein on MDSCs . In animal models of colorectal cancer, CXCR2 influences MDSCs migration and recruitment toward tumors by up‐regulating chemotactic factors CXCL1 and CXCL2 .…”

Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency

“…Increased production of granulocyte macrophage colony-stimulating factor (GM-CSF) has been observed in the mucosa of patients with inflammatory bowel disease and rodents subjected to experimental colitis. GM-CSF was also shown to promote the generation of myeloid-derived suppressor cells (19). We cultured bone marrow neutrophils from WT or Tollip -/mice in GM-CSF overnight, and subsequently cocultured with CFSE-labeled allogeneic splenocytes in anti-CD3-coated plates.…”