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IL-30: A cytokine that promotes cancer development
IL-30: A cytokine that promotes cancer development. IL-30 was discovered in 2002, with a molecular mass of about 28kDa. IL-30 constitutes a heterodimeric cytokine four alpha helix subunit of IL-27, also known as IL-27p28 (Reference 1).
In humans and mice, IL-30 interacts with IL-27β subunit EBI3 through non-covalent bonds to form biologically active IL-27, which acts through IL-27R activation. IL-27 has the dual effects of promoting tumor and anti-tumor.
Of course, IL-30 and EBI3 are non-covalently bonded, IL-30 can be dissociated, as an independent cytokine, directly bind to gp130, inhibit its signal, and antagonize the anti-tumor effect of IL-27 (Reference 3). The independent IL-30 is mainly to promote the role of tumor.
In addition, IL-35 and IL-27 share β subunit EBI3, and IL-35 is an important cytokine secreted by Breg, and its main role is to promote tumor formation and metastasis.
Myeloid cells, including macrophages, monocytes, microglia and giant cells, are activated by various microorganisms and immunostimulants (TNF family members CD40 and CD137, type I and type I and type II IFNs). The main cell source of IL-30/IL-27p28 can also be produced by neutrophils, endothelial and epithelial cells.
IL-27 receptor expression
IL-27R contains the ligand binding chain IL-27Ra (WSX-1, TCCR), (expressed on DC cells, monocytes, macrophages, mast cells, eosinophils, T, B and NK cells, cell activation Later upregulation), and the signal transduction chain gp130 (expressed in almost all cell types).
A variety of cancer cells also express IL-27R and respond to IL-27 stimulation. The latter can inhibit the proliferation, migration and invasion of tumor cells, and promote the death of apoptosis, which directly exerts an anti-tumor effect. The binding of IL-27 to its receptor can activate the JAK-STAT signaling pathway and immunomodulatory function.
Immunomodulatory function as IL-27 subunit
As the source and target of IL-27, myeloid cells participate in its anti-tumor and tumor-promoting activities, which will depend on the specific type of tumor and the function of myeloid cells.
In a human non-small cell lung cancer xenograft model, IL-27 down-regulates the expression of tumor stem cells and epithelial-mesenchymal metastasis (EMT) related genes, and also re-educates the intratumoral myeloid cells to play an anti-tumor effect.
IL-27 promotes the differentiation of human monocytes into macrophages and enhances the production of pro-inflammatory cytokines, such as IL-6, TNF-a, MIP-1α and MIP-1β.
IL-27 also up-regulates HLA-E, interacts with CD94/NKG2A, inhibits NK cell function and IFN release, which in turn weakens anti-tumor immunity. IL-27 can also up-regulate perforin and promote the cytotoxicity of NK cells. On the contrary, it inhibits the activity of CD56 bright NK cell subsets.
IL-27 can up-regulate the expression of PD-L1/2 and IDO, inhibit T cell function, and induce exhaustion. In addition, it can induce CD4+ T cells to produce IL-10 and IL-17. IL-27 can promote the production of IL-10 by Th1, Th2, Th17, Treg and Tr1 cell subsets, activate the inhibitory activity of myeloid cells, and thereby inhibit Production of macrophages and inflammatory cytokines.
IL-27 has the environment-dependent activation and suppression functions in innate immunity, and emphasizes its role in limiting the activation of macrophages through inflammatory cytokines and maintaining immune homeostasis.
The activity of IL-27 and the results produced are highly dependent on the cell type, activation state and microenvironment.
The role of IL-30/IL-27p28 in tumor microenvironment
The figure above clearly indicates that IL-30 up-regulates cytokines (IL-1β, IL-6, IL-8, etc.), chemokines (CXCL1/2/10, etc.), immune checkpoint (PD-L1), and down-regulates Tumor suppressor genes (PTEN, etc.).
IL-30/IL-27p28 acts directly or indirectly through the above-mentioned secondary cytokines to achieve crosstalk between cancer cells and myeloid suppressor cells, and IL-30/IL-27p28 promotes cancer stem cell niches, thereby promoting tumor immune escape and tumor progression .
Although IL-30/IL-27p28 in the tumor microenvironment mainly promotes tumors, neutralization is one of the targeted treatment strategies. However, because IL-30/IL-27p28 is widely expressed, as the α subunit of IL-27, it has anti-tumor activity. How to avoid the off-target toxicity of its inhibitors needs to be considered in the development strategy, such as the use of antibody prodrug technology, nano-drug delivery systems, etc.
(source:internet, reference only)