A new research perspective was published in the journal Oncotarget, entitled, “The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy.”
CD200 is an immunoregulatory cell surface ligand with proven pro-tumorigenic credentials via its ability to suppress CD200 receptor (CD200R)-expressing anti-tumour immune function. This definitive role for the CD200-CD200R axis in regulating an immunosuppressive tumour microenvironment has garnered increasing interest in CD200 as a candidate target for immune checkpoint inhibition therapy.
However, while the CD200 blocking antibody samalizumab is still in the early stages of clinical testing, alternative mechanisms for the pro-tumorigenic role of CD200 have recently emerged that extend beyond direct suppression of anti-tumour T cell responses and, as such, may not be susceptible to CD200 antibody blockade.
In this new research perspective, researchers Anqi Shao and David M. Owens from Columbia University Irving Medical Center summarised the current understanding of CD200 expression and function in the tumour microenvironment as well as alternative strategies for the potential neutralisation of multiple CD200 mechanisms in human cancers.
“In the future, unbiased genomic- and proteomic-based approaches may help to clarify these issues by identifying tumour-specific mechanisms of CD200 expression regulation across a variety of human cancers that may be leveraged for broader therapeutic benefit.”
The CD200-CD200R axis in the central nervous system (CNS) plays a key role in facilitating communication between neurons and microglia to keep inflammation in check. Researchers have identified multiple pathways that regulate CD200 expression in the CNS. In astrocytes and neurons, CD200 expression is regulated by FGFR1 activation, which is essential for controlling neuroinflammation. Treatment with PPARγ ligands can also suppress CD200 induction in activated glial cells, which is believed to contribute to PPARγ-mediated neuroprotection.
Pathological conditions can also affect CD200 expression in microglia, with IFNγ from a leaky blood-brain barrier inhibiting CD200 expression. In other tissues, the regulation of CD200 expression is more diverse, with each cell lineage having its own unique set of regulatory molecules. CD200 expression can be induced by p53 during caspase-dependent dendritic cell apoptosis and by TLR4 and NF-κB signalling in a mouse model of meningococcal infection. In bone marrow mesenchymal stem cells, CD200 expression can be activated by osteogenic and pro-inflammatory cytokines in an NF-κB-dependent manner. In the skeletal system, CD200 expression in osteoblasts is dependent on IL15RA signalling, while in the lung, airway epithelial cell and capillary endothelial cell expression of CD200 is regulated by corticosteroids. In hair follicle epithelial progenitors, CD200 expression is linked to β1 integrin activation.
In the world of oncology, there are significant gaps in our understanding of the regulation of CD200 expression in human cancers. Despite numerous studies, researchers have yet to fully comprehend the regulation of CD200 expression in various tumour types.
One challenge is the limited information available on CD200 expression regulation in cancers, compared to normal tissue. Additionally, CD200 expression can occur at different stages of tumour development and may only be present in a subset of cancer cells. This complexity makes it difficult to identify potential targets to block CD200 expression.
Recent findings in metastatic melanoma suggest that CD200 is regulated by ERK activation, which is triggered by N-RAS or B-RAF mutations. This suggests that CD200 induction may be an early event in melanoma pathogenesis. In other tumour types, such as human and murine cSCC, CD200 expression is induced in the later stages of tumour progression. In endometriosis patients, CD200 expression is upregulated in lesional stromal cells and can be further increased by 17β-estradiol treatment.
In colorectal carcinoma cells, CD200 expression is dependent on the activity of FMNL2, a Rho GTPase effector protein. Meanwhile, a polymorphism in miR-499a has been identified as a poor prognostic factor for non-small cell lung cancer cases that exhibit elevated CD200 expression.
These findings highlight the need for further research to better understand the regulation of CD200 expression in human cancers and to identify potential targets for therapeutic intervention.
