A paper in Science Advances in August 2024 describes XPO1 (Exportin-1/CRM1) as a “bona fide tumour antigen” recognised by natural killer (NK) cells. With implications for vaccine development, the research identifies an opportunity for a personalised approach to NK cell therapy for solid tumours. The authors, led by a team at the University of Southampton, believe that “hijacking” the protein is a viable avenue of investigation.
Natural killer cells
The paper states that natural killer (NK) cells are becoming “increasingly recognised for their anticancer activity”. Their functions are “tightly controlled by a diverse repertoire of cell surface receptors”. Killer cell immunoglobin-like receptors (KIRs) are an “important family” of NK cells receptors, forming a polymorphic family of receptors with human leukocyte antigen (HLA) class I ligands. KIRs are “implicated in susceptibility to, and the outcome of”, a range of cancers, and contribute to heterogeneity within the innate immune response to malignancy.
KIRs can be activating or inhibitory; although the HLA class I ligand specificities of the inhibitory KIR are “relatively well defined”, the ligand specificities of the activating KIR are “much harder to identify”. However, recent research suggests that activating KIR can have an HLA class I-restricted peptide specificity. KIRs recognise families of peptide:HLA complexes in a motif-based manner, which allows recognition of different combinations of peptide and HLA.
Activating KIRs have been linked to protective responses to several cancers, including haematological malignancies. There is “potential” for KIR2DS2 binding peptides to be tumour-associated antigens derived from endogenously expressed proteins that are up-regulated during tumorigenesis. In the context of a lack of cancer-associated peptides that bind activating KIR, the authors sought to investigate this in a proof-of-concept study.
The study
XPO1, a nuclear export protein, is “frequently overexpressed” in cancer and serves as a “driver of oncogenesis”. The paper describes a molecular mechanism underlying a KIR2DS2 specific response against cancer, identifying that the combination of XPO1 and NK cells is associated with longer survival in “multiple” cancers. XPO1 is expressed at “low” levels in healthy cells, which the authors infer are too low to generate an activating signal in KIR2DS2-positive NK cells. They propose that the up-regulation of XPO1 found in cancer can “alter the balance” for NK cell activation in favour of activation of KIR2DS2-positive NK cells.
Professor of Hepatology at the University of Southampton, Salim Khakoo, challenges previous assumptions that killer cells attack cancer cells randomly.
“Our findings actually show how our body’s immune system recognises and attacks these cancer cells.”
Killer cells as “emerging” as a form of immunotherapy that “shows huge promise”, says Professor Khakoo.
“They don’t attack health tissue in the way chemotherapy and other immunotherapies do, so are safer and have [fewer] side-effects than traditional forms of cancer treatment.”
The peptide derived from XPO1 appeared to attract natural killer cells to trigger an immune response, leading to “significantly better survival rates” across a “range of cancers”. This included cancers with higher rates of death, such as liver cancer. Professor Ralf Schittenhelm of Monash University hopes that the research offers a new way of activating killer cells to treat disease effectively.
“We hope it could lead to personalised cancer treatment, especially in cases where traditional therapies have failed. The potential to develop targeted therapies that utilise the body’s own immune system is incredibly exciting.”
The team at Southampton will move to vaccine development in pursuit of the “first vaccine that uses natural killer cells to fight cancer”.
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