Investigation into th NK cell Immunomodulatory activity of XP01 inhibitors

Nuclear export is an important process for regulating transcription and translation by spatial distribution of transcription factors and RNA. Exportin-1 (XPO1) is a nuclear export protein that transports key tumour suppressor proteins, oncogenic mRNA and ribosomal constituents and is often dysregulated in haematological malignancies to promote cancer cell survival and proliferation. Selinexor is a first-in-class inhibitor of XPO1 and is approved for the treatment of relapsed and refractory multiple myeloma and diffuse large B cell lymphoma. Selinexor promotes accumulation of tumour suppressor proteins in the nucleus and inhibition of oncogenic protein translation leading to cancer cell apoptosis. It is beginning to be appreciated that small molecule drugs which target tumorigenic pathways can also possess immunomodulatory activity and understanding this can improve the design of drug combination strategies. This project aimed to understand how XPO1 inhibition impacts the NK cell immune response against malignant B cells to aid the design of powerful combination therapy strategies to improve the treatment of patients with cancer. XPO1 inhibition in B cell lymphoma and multiple myeloma cell lines and primary chronic lymphocytic leukaemia cells sensitised cancer cells to NK cell cytotoxicity. Increased sensitivity to NK was largely due to decreased surface expression of HLA-E, the ligand for the inhibitory NK cell receptor NKG2A. As such, XPO1 inhibition led to predominant activation of NKG2A+ NK cells and potentiated antibody-dependent cellular cytotoxicity in combination with clinically relevant monoclonal antibodies. This research project also identified that CLL cells encounter signals within the lymph nodes of patients which decreases their sensitivity to NK cell activation through upregulation of HLA-E. Overall, this research project revealed a novel immunomodulatory mechanism of XPO1 inhibition in haematological malignancies by sensitising cancer cells to NK anti-tumour functions via disruption to the NKG2A:HLA-E axis. Future work should explore the in vivo contribution of NK cells to selinexor efficacy and investigate selinexor-NK cell therapeutic strategies to improve the outcomes of selinexor treatment.