The Role of Fc Receptor Neonatal in Cancer

The Fc receptor neonatal (FcRn) has long been recognized for its pivotal role in the immune system, specifically in the transportation of immunoglobulin G (IgG) across various cellular barriers. Recent research has unveiled a new dimension to FcRn's influence, particularly in the context of cancer growth. Targeted therapy of cancer has made promising advances over recent years, but tumour heterogeneity, cellular mutagenesis and drug resistance are remaining challenges. FcRn may offer targeted anti-tumour approaches dependent on FcRn expression levels. This article highlights insights of recent publications from Cadena Castaneda et al. and Rudnik-Jansen et al., among others.

FcRn Role in Cellular Recycling

Human serum albumin (HSA) stands out as the predominant plasma protein, functioning as a natural carrier for endogenous molecules like bilirubin and fatty acids, thanks to its numerous ligand-binding sites. In contrast, immunoglobulin G (IgG) represents the most prevalent antibody class, constituting approximately 10–20% of plasma proteins. Within the vascular endothelium, FcRn plays a crucial role in preserving serum levels of IgG and HSA by orchestrating a cellular recycling and endosomal sorting process that prevents the degradation of these ligands in lysosomes.

FcRn Role in Immunosurveillance

FcRn also plays a distinctive role in cancer immunosurveillance. Tumor‐specific immune checkpoints were cross‐presented in an FcRn‐dependent manner, and CD8+ T‐cell‐mediated tumor clearance relied on the presence of tumor‐specific antibodies. In a murine model of spontaneous colorectal cancer, homozygous inactivation of FCGRT led to increased tumor progression and metastasis. A similar study reveals that dentritic cells lacking FCGRT epxression show less capacity do build IL-12 . As a result, infiltrating CD8+ T-cells were less effective, exhibiting a diminished response when stimulated with CD3 and CD28. In summary, the downregulation of FcRn in immune cells can result in defective immune responses.

FcRn as Marker for Cancer

FcRn has potential as a bio marker for cancer cells. Studies have indicated that FcRn is not only expressed by immune cells but also by cancer cells themselves. The receptor is expressed at the cell surface and can be marked with the help of antibodies. Co‐staining of FcRn and cytokeratin in the intraoperatory biopsies could be a possible solution to help detect and remove hard to find micrometastases.

Moreover, the dysregulation of FcRn in cancer cells may influence the tumor microenvironment and immune evasion strategies. Elevated levels of FcRn expression have been correlated with aggressive tumor phenotypes and poorer prognosis in certain cancers, such as lung and colorectal cancer, further highlighting its significance as a potential biomarker for cancer diagnosis and prognosis.

FcRn Dysregulation in Cancer Pathophysiology

FcRn dysregulation has been described in several cancer types. Downregulation could be associated with increased tumor growth and metastasis. Especially in breast, prostate, and lung cancer FcRn expression was impaired. As described above, FcRn is vital for Albumin recovery in normal cells. The lack of FcRn induces pinozytosis; Albumin is beeing catabolized instead of being recycled (2b). The albumin serves now as fuel for tumor growth in order to sustain its high metabolic requirements. The oncogenic RAS mutations frequently occur in human tumours of which KRAS is the predominant mutated isoform in PDAC. FcRn knockdown in tumour cell lines with detectable FcRn expression resulted in increased intracellular HSA levels, conversely, increased FcRn levels exhibited lower intracellular HSA levels.

Paradoxically, it seems that FcRn overexpression also increases tumor growth (1a). Albumin plays here an important role again, however this time indirectly as nutrient cargo. It imports important substrates such as fatty acids and thyroxin which are vital for tumor growth.

Therapeutic Implications

The recognition of FcRn's role in cancer growth opens up exciting possibilities for therapeutic interventions. Targeting FcRn expression or function could disrupt the intricate balance that supports cancer cell survival and proliferation. However diminished expression of this receptor correlates with weakened immunosurveillance, while dysregulation of FcRn in cancer cells fosters tumor growth. Accordingly, depending on this dysregulation, albumin-based drug conjugates hold promise for treating tumors that exhibit aberrant FcRn activity.

In environments where FcRn expression is upregulated the drug conjugate benefits from higher uptake; in downregulated environments of KRAS mutated cancer cells macropinocytosis can be exploited and increases the susceptibility to antibody-drug conjugates or albumin-drug designs. Half-life extension mediated by FcRn engagement likely increases the passive tumour accumulation process of both endogenous HSA binding drugs and HSA drug conjugates. Cytotoxic drugs modified with a maleimide side chain have been designed to bind to the endogenous HSA pool for enhanced tumour accumulation.

Full size monoclonal antibodies (mAbs) that engage with FcRn and cancer cell receptors offer long-acting targeted therapy. Antibody-drug conjugates combining the specificity of mAbs with a cytotoxic drug offer increased potency. MAb-dependent effector cell activation relies on Fc binding to the Fc-gamma Receptor (FcγR) resulting in antibody-dependent cellular phagocytosis and antibody-dependent cell-mediated cytotoxicity.

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