Modulation of anti-tumour immunity by XPO1 inhibitors

Abstract

Exportin-1 (XPO1) is a nuclear export protein that, when overexpressed, can facilitate cancer cell proliferation and survival and is frequently overexpressed or mutated in cancer patients. As such, selective inhibitors of XPO1 (XPO1i) function have been developed to inhibit cancer cell proliferation and induce apoptosis. This review outlines the evidence for the immunomodulatory properties of XPO1 inhibition and discusses the potential for combining and sequencing XPO1i with immunotherapy to improve the treatment of patients with cancer. Selinexor is a first-in-class XPO1i that is FDA-approved for the treatment of patients with relapsed and refractory (RR) multiple myeloma and RR diffuse large B cell lymphoma. In addition to the cancer cell intrinsic pro-apoptotic activity, increasing evidence suggests that XPO1 inhibition has immunomodulatory properties. In this review, we describe how XPO1i can lead to a skewing of macrophage polarisation, inhibition of neutrophil extracellular traps, modulation of immune checkpoint expression, blockade of myeloid-derived suppressor cells (MDSCs) and sensitisation of cancer cells to T cell and NK (natural killer) cell immunosurveillance. As such, there is an opportunity for selinexor to enhance immunotherapy efficacy and thus a need for clinical trials assessing selinexor in combination with immunotherapies such as immune checkpoint inhibitors, direct targeting monoclonal antibodies, chimeric antigen receptor (CAR)-T cells and cereblon E3 ligase modulators (CELMoDs).

Keywords: ADCC; CAR-NK; CAR-T; Exportin-1 (XPO1); immunotherapy; selinexor.

Figure 1

Selinexor enhances NK cell function. Treatment of malignant B cells with selinexor has been shown to enhance NK cytotoxicity via downregulation of HLA-E, decreasing interactions with the inhibitory NK cell receptor NKG2A. When combined with clinically relevant monoclonal antibodies targeting tumour-associated antigens (TAAs), selinexor enhanced ADCC of opsonised targets. ADCC: antibody-dependent cellular cytotoxicity; NK: natural killer; mAb: monoclonal antibody. Parts of this figure were adapted from pictures provided by Servier Medical Art (https://smart.servier.com/) under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/)

Figure 2

Selinexor promotes bsAb and CAR-T cell function. (A) Selinexor has been shown to sensitise TRAIL-R2⁺ breast cancer cells to CD3xTRAIL-R2 bispecific antibodies (bsAb); (B) in vitro and pre-clinical data have demonstrated that CAR-T cell function is enhanced when cancer cells are pre-treated with selinexor. Clinical trials are ongoing to combine selinexor treatment with adoptive transfer of anti-CD19 CAR-T and anti-BCMA CAR-T cells. TAA: tumour-associated antigen; TCR: T cell receptor; CAR: chimeric antigen receptor; BCMA: B cell maturation antigen; TRAIL: TNF-related apoptosis-inducing ligand. Parts of this figure were adapted from pictures provided by Servier Medical Art (https://smart.servier.com/) under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/)