Journal Article

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression

Blunt, Matthew D, Doyle, Amber D. P, Sale, Ben, Walker, Christopher J, Cragg, Mark S, Fisher, Jack G, Graham, Lara V, Del Rio, Luis, Johnson, Peter W. M, coni, Francesco, Landesman, Yosef, Sonar, Shreyanshi, Henderson, Isla, Khakoo, Salim. I

2023

Overview

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.

• Publisher: Nature Publishing Group
• Subject: Apoptosis / CD40L protein / Cell activation / Chronic lymphocytic leukemia / Cytotoxicity / Death receptors / Down-regulation / Histocompatibility antigen HLA / Immunotherapy / Inhibitor drugs / Inhibitors / Leukemia / Lymph nodes / Lymphocytes / Lymphocytes T / Lymphoma / Monoclonal antibodies / Natural killer cells / Non-Hodgkin's lymphoma / Rituximab / Targeted cancer therapy / Toxicity / Tumor suppressor genes / Tumors / Up-regulation