CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Modulation of anti-tumour immunity by XPO1 inhibitors.
Modulation of anti-tumour immunity by XPO1 inhibitors.
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输出蛋白1（XPO1）是一种核输出蛋白，其过表达可促进癌细胞增殖和存活，并且在癌症患者中常见过表达或突变。因此，研究者开发了选择性XPO1抑制剂（XPO1i），用于抑制癌细胞增殖并诱导凋亡。本综述概述XPO1抑制的免疫调节特性证据，并讨论将XPO1i与免疫疗法联合及序贯使用以改善癌症患者治疗的潜力。Selinexor是首创XPO1i，已获美国食品药品监督管理局批准用于复发/难治性（RR）多发性骨髓瘤及弥漫性大B细胞淋巴瘤。除癌细胞内在的促凋亡作用外，越来越多证据表明XPO1抑制具有免疫调节特性。本文介绍XPO1i如何改变巨噬细胞极化、抑制中性粒细胞胞外诱捕网、调节免疫检查点表达、阻断髓源性抑制细胞（MDSC），以及增强癌细胞对T细胞和自然杀伤（NK）细胞免疫监视的敏感性。
因此，selinexor有望增强免疫治疗疗效，亟需开展临床试验评估其与免疫检查点抑制剂、直接靶向单克隆抗体、嵌合抗原受体（CAR）T细胞及cereblon E3连接酶调节剂（CELMoD）等免疫疗法联合的效果。
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).
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