Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets, including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells acting as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathological conditions. Insufficient GM-CSF hinders the proper production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses. Conversely, excessive GM-CSF can deplete immune cells and promote cancer growth.
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GM-CSF Orchestrating Immune Cell Homeostasis and Response
GM-CSF is produced by various cell types in response to immunogenic stimuli, and its receptor (GM-CSFR) is expressed on myeloid cells, B cells, and non-hematopoietic cells. GM-CSFR activation involves JAK2-mediated signaling, leading to downstream events such as STAT5 phosphorylation and activation of PI3K and MAPK pathways. The intricate phosphorylation patterns of the beta chain of GM-CSFR dictate the activation of specific downstream pathways, influencing cell survival, proliferation, and differentiation.
Fig. 1 Signaling downstream of the GM-CSF receptor in myeloid cells (Kumar A., et al. 2022).
GM-CSF is a pivotal player in immune cell homeostasis, intricately regulating myelopoiesis and influencing the functions of both myeloid and non-myeloid cells in diverse immunological contexts. In the context of myelopoiesis, GM-CSF plays a crucial role in driving emergency myelopoiesis in response to infections, cancer, and stress. It regulates the generation of monocytes, which develop into macrophages and dendritic cells, and polymorphonuclear neutrophils (PMNs). Monocyte production is enhanced under inflammatory conditions, and GM-CSF blockade alters monocyte profiles, shifting them towards an immunomodulatory phenotype.
GM-CSF's impact on PMNs, key innate immune cells, is evident in its direct stimulation of neutrophil proliferation. GM-CSF-deficient mice show impaired control of infections, emphasizing the importance of GM-CSF in orchestrating an effective immune response.
Furthermore, GM-CSF supports the development and differentiation of dendritic cells (DCs), critical antigen-presenting cells that bridge innate and adaptive immunity. GM-CSF influences the expansion of specific DC subsets in various tissues, shedding light on its nuanced role in shaping the immune landscape.
The Dual Role of GM-CSF in Cancer
The cytokine Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) plays a dual role in cancer development, acting as both a promoter and inhibitor of tumor progression. Its effects are diverse, influencing various immune and non-immune cell types, thus modulating cell-intrinsic and cell-extrinsic processes during cancer development. The dichotomy of GM-CSF's impact is evident in its association with both favorable clinical prognosis, as observed in colorectal cancer, and increased aggressiveness in other cancers like bladder cancer, colorectal carcinoma, glioblastomas, and head and neck cancers.
Understanding GM-CSF's intricate functions in different cancer types is crucial for developing effective therapeutic strategies. The cytokine's therapeutic effects are exemplified in its ability to stimulate anti-tumor immune responses. GM-CSF restores neutrophil-driven immune responses, activates anti-tumorigenic macrophages and dendritic cells, and promotes anti-cancer T cell responses. Additionally, GM-CSF directly inhibits tumor cell growth, induces differentiation, and inhibits angiogenesis.
Nevertheless, the deleterious effects of GM-CSF are of significant importance. It plays a role in fostering a microenvironment conducive to tumor growth by encouraging the development of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs). GM-CSF also exerts control over immune checkpoints, including the expression of PD-L1, thereby supporting immunosuppressive functions. Additionally, GM-CSF promotes epithelial-to-mesenchymal transition (EMT) and angiogenesis, thereby contributing to the progression of cancer.
To counter the pro-tumorigenic effects of GM-CSF, diverse strategies are being investigated. These approaches encompass direct targeting of GM-CSF or its receptor through the use of neutralizing antibodies, as well as the inhibition of downstream effectors in the GM-CSF signaling pathway. For example, the blockade of GM-CSFRα prevents the polarization of monocytes into MDSCs expressing PD-L1. The overarching goal of these methods is to transform the tumor microenvironment from an immunosuppressive state to an anti-tumorigenic one, thereby reinstating effective tumor immunosurveillance.
In conclusion, achieving a delicate equilibrium between the immunostimulatory and inhibitory effects of GM-CSF is pivotal for enhancing the effectiveness of GM-CSF-based cancer treatments and ultimately improving patient outcomes. Current research endeavors are focused on refining these strategies, with the aim of unlocking the full potential of GM-CSF in the field of cancer therapy.
References
- Kumar A.; et al. GM-CSF: A double-edged sword in cancer immunotherapy. Frontiers in Immunology. 2022, 13: 901277.
- Yan W. L.; et al. Recent progress in GM-CSF-based cancer immunotherapy. Immunotherapy. 2017, 9(4): 347-360.
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