Investigation into the immunomodulatory activity of XPO1 inhibitors

Abstract

Nuclear export is an important process for regulating transcription and translation by spatial distribution of transcription factors, RNA and signalling components. Exportin-1 (XPO1) is a nuclear export protein that transports key tumour suppressor proteins, oncogenic mRNA and ribosomal constituents into the cytoplasm and its function 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 induces the accumulation of tumour suppressor proteins in the nucleus and inhibits oncogene translation to impair cell proliferation and induce apoptosis. It is beginning to be appreciated that small molecule drugs which target tumourigenic pathways also possess immunomodulatory activity. Understanding the mechanism behind these immunomodulatory effects can improve the design of rational combination strategies with immunotherapies. Selinexor has been shown to enhance T cell function, increase NK cell abundance in tumours and promote tumour regression in combination with PD-1 blockade. But how XPO1 inhibition impacts NK cell-mediated immunity is unknown, which this project aimed to address, with the hypothesis that XPO1 inhibition sensitises cancer cells to NK cell immunosurveillance via modulation of NK cell ligand expression. 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 cell activation was due to decreased surface expression of HLA-E, the ligand for the inhibitory NK cell receptor NKG2A. As such, XPO1 inhibition led to preferential activation of NKG2A+ NK cells and potentiated the effects of expanded allogeneic NK cells, anti-CD19 CAR NK cells and promoted antibody-dependent cellular cytotoxicity in combination with clinically relevant monoclonal antibodies. This research project also identified that lymph node-associated signals IL-4 and CD40L confer resistance of malignant B cells to NK cell activation through upregulation of HLA-E, and this can be reversed by XPO1 inhibition.Overall, this research project revealed a novel immunomodulatory mechanism of XPO1 inhibition in haematological malignancies by sensitising cancer cells to NK cell anti-tumour functions via disruption of NKG2A:HLA-E interactions. Future work could investigate the combination of selinexor with NK cell therapeutic strategies in vivo to assess the potential for translation of these findings to clinical trials.<br/