Granulocyte-macrophage colony stimulating factor (GM-CSF) is a monomeric glycoprotein and functions as a cytokine controlling the production, differentiation, and function of granulocytes and macrophages. Critical role of GM-CSF is in immune modulation and hematopoiesis. GM-CSF was first identified in mouse in 1985 by molecular cloning. Naturally occurring GM-CSF have pharmaceutical analogs namely sargramostim and molgramostim. GM-CSF, also known as colony-stimulating factor 2 (CSF2), is secreted by various cells such as macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts. Protein encoded by CSF2 gene in its active form is a homodimer and is found in the extracellular region. GM-CSF has its relevance and importance in various diseases such as inflammatory, infectious and autoimmune diseases; associated human inflammatory diseases includes rheumatoid arthritis, inflammatory renal disease and inflammatory lung disorders. CSF2 is associated with diseases such as pulmonary alveolar proteinosis and mucositis. Protein encoded by CSF2 gene also has its relevance with SARS-CoV-2 as elevated levels of cytokines have been detected in SARS-CoV-2 infected patients that develop acute respiratory distress syndrome. In the context of cancer, GM-CSF is frequently upregulated in multiple types of human cancers such as small-cell lung carcinomas, meningiomas, skin carcinoma, gliomas, and head and neck squamous cell carcinomas (HNSCC). In this article, we have shed light on the importance of GM-CSF and its association with different cancers.
Genomic location and Expression of GM-CSF
Gene encoding GM-CSF is found in the genomic loci of 5q31. The gene is in close proximity to IL-3 gene. These two genes are part of cytokine gene cluster at 5q31 and this cluster of related genes is associated with interstitial deletions in the 5q-syndrome and acute myelogenous leukemia. This cluster has several other genes that encodes IL-4, IL-5 and IL-13. Cytokines play a major role in the regulation of GM-CSF expression. Lipopolysaccharide and pro-inflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor-α stimulate the expression of GM-CSF, however the expression of GM-CSF is inhibited by IL-4, IL-10 and IFN-γ.
GM-CSF and Immunity
One of the critical roles of GM-CSF is the regulation of anti-tumor immune responses. This is achieved by activating the two broad categories of immunity, innate and adaptive immunity. Cancer cells capable of producing GM-CSF stimulate specific anti-tumor immunity which are potent and long-lasting, and this is carried out by priming CD4+ and CD8+ T cells to recognize circulating tumor-associated antigens and this in turn induces systemic antitumor-specific immune response.
GM-CSF has both immune dependent and immune independent effects. Among the immune dependent effects, primary functions of GM-CSF include stimulating dendritic cells and also working as an immunomodulator by regulating monocytes/macrophages. GM-CSF also has various roles in the immune independent mechanism and works with functions associated with tumor inhibitory roles and it also works as a tumor stimulating factor. GM-CSF works in an autocrine or paracrine manner as a tumor stimulating factor. In the inhibitory role, GM-CSF inhibits tumor growth, metastasis and angiogenesis.
Role of GM-CSF in Cancer
Amongst the various cancer conditions, GM-CSF plays an important role in glioblastoma. Glioblastoma is a WHO grade IV glioma and known for its aggressiveness and low survival rate in patients. Previous studies have shown increased levels of GM-CSF in malignant glioblastoma specimen has significant correlation with poor prognosis. GM-CSF signals via STAT proteins. STATs are Signal Transducers and Activators of Transcription. In macrophages GM-CSF signals via STAT3. In glioblastoma, GM-CSF and the associated receptor promote tumor progression via STAT3 signaling pathway. GM-CSF is secreted by tumor-associated microglial cells in the tumor environment. It has also been shown that lower levels of GM-CSF results in suppression of cancer cell growth and metastasis. Sielska et al. has shown that CSF2 expression is higher in a subset of mesenchymal glioblastomas as well as in cultured human glioma cells and they have shown that CSF2 signaling would possibly be a novel target for glioblastoma therapy.
In addition to Glioblastoma, GM-CSF has important roles in other cancers such as bladder cancer, colorectal cancer and head and neck cancer among others. In urothelial cancers it has been found that GM-CSF receptors are expressed concomitantly and are a reason for the aggressiveness for these carcinomas as the increased expression results in an autocrine and/or paracrine stimulation of growth. In some patients with colorectal cancer, higher levels of GM-CSF are found suggesting that it may be an independent prognostic factor. Increased expression of GM-CSF is significantly correlated with poor prognosis in patients with squamous cell carcinoma of the head and neck (HNSCC).
Although study of GM-CSF is an interesting area of cancer research and numerous studies have shown significant findings, further research is warranted to understand the biological mechanisms underlying tumor specific inhibitory and stimulatory effects in detail. In addition, not much is known about the link between GM-CSF and T cells, and advancement in this area will help us understand the basic biology of GM-CSF and also help to elucidate the clinical applications.
Written by: Pawan Patro, PhD
Keywords: GM-CSF, CSF2, cytokine, expression, cancer, immunity