Granulocyte macrophage colony-stimulating factor has come of age: From a vaccine adjuvant to antiviral immunotherapy

Abstract

GM-CSF acts as a pro-inflammatory cytokine and a key growth factor produced by several immune cells such as macrophages and activated T cells. In this review, we discuss recent studies that point to the crucial role of GM-CSF in the immune response against infections. Upon induction, GM-CSF activates four main signalling networks including the JAK/STAT, PI3K, MAPK, and NFκB pathways. Many of these transduction pathways such as JAK/STAT signal via proteins commonly activated with other antiviral signalling cascades, such as those induced by IFNs. GM-CSF also helps defend against respiratory infections by regulating alveolar macrophage differentiation and enhancing innate immunity in the lungs. Here, we also summarize the numerous clinical trials that have taken advantage of GM-CSF's mechanistic attributes in immunotherapy. Moreover, we discuss how GM-CSF is used as an adjuvant in vaccines and how its activity is interfered with to reduce inflammation such as in the case of COVID-19. This review brings forth the current knowledge on the antiviral actions of GM-CSF, the associated signalling cascades, and its application in immunotherapy.

Keywords: IFN; Pro-inflammatory cytokines; Vaccine; Virus.

Graphical abstract

Fig. 1

GM-CSF signaling pathways. To activate downstream signalling, multiple events occur as depicted (1-4) in this Fig. 1) GM-CSF binds to the α subunit of the GM-CSFR. 2) Dimerization of the two subunits upon GM-CSF binding. 3) Formation of the GM-CSFR hexameric complex followed by the lateral association of two hexameric complexes. 4) Several signalling pathways could result from GM-CSFR activation; JAK2 binds the β cytoplasmic tails and transphosphorylate each other, which activates the PI3K, MAPK, and JAK/STAT pathways, as well as the NFκB pathway. Activated NFκB dimers translocate into the nucleus and result in the transcription of genes for the differentiation and survival of myeloid cells such as RelB and IRF4. The JAK/STAT pathway induces the phosphorylation of STAT5, eventually causing STAT5 dimerization and translocation to the nucleus for transcriptional regulation of genes for the differentiation, proliferation, and survival of myeloid cells including c-fos, RelB, IRF4, pim-1, cis, and osm. The MAPK pathway also results in the differentiation and survival of myeloid cells via ERK kinase activation, through the transcription of genes such as c-fos. Finally, PI3K is phosphorylated by JAK2 resulting in signal transduction through a PIP3 intermediate, causing membrane recruitment of PKB followed by its phosphorylation by mTORC2 and PDK1, eventually leading to the proliferation and survival of myeloid cells.