肿瘤细胞治疗研究
英文原题：Cyclophosphamide-pomalidomide combination alters the tumour cell secretome and enhances the anti-myeloma activity of elotuzumab through NK cell-mediated cytotoxicity.
这些发现支持在含 ELO 的 MM 方案中加入 CTX，并为将 POM 与免疫检查点阻断联合以最大化 NK 对 MM 的细胞毒性提供了依据。
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，尽管近年来治疗选择取得进展，但仍在很大程度上无法治愈。Elotuzumab（ELO）是一种人源化 IgG1 单克隆抗体，靶向信号淋巴细胞激活分子 F7（SLAMF7）的胞外结构域。虽然 ELO 单药显示出中等程度的单药活性，但与免疫调节药物（IMIDs）如 lenalidomide 和 pomalidomide（POM）联合已被证明在治疗 MM 中有益。然而，仍需进一步研究以寻找最佳联合策略来提高疗效。我们评估了 cyclophosphamide（CTX）与 POM 联合以及 ELO 单用或与新型免疫检查点抑制剂联合对 NK 细胞介导的抗 MM 效应的影响。从 cyclophosphamide 处理的（CTX）或 pomalidomide 处理的 MM 细胞（POM）或两者联合处理（CTX+POM）中收集肿瘤细胞分泌组（TCS）。原代人 NK 细胞用 TCS CTX、TCS POM 或 TCS CTX+POM 条件化，并评估 NK 表型、迁移和细胞毒性。我们表明，CTX 单用或与 POM 联合可改变 MM 细胞的肿瘤分泌组，并促进 NK 细胞募集和抗肿瘤细胞毒性。CTX 和 POM 处理维持了 MM 细胞上 SLAMF7 的表达，暴露于来自 MM 细胞的 TCS CTX 或 CTX+POM 的 NK 细胞增强了 ELO 在增强 NK 介导的细胞毒性中的作用。暴露于来自 MM 细胞的 TCS CTX 或 CTX+POM 的 NK 细胞增强了 NK 细胞对 MM 细胞的细胞毒性，并诱导 MM 细胞上 PD-L1 和 CD47 的表达。使用抗 PD-1 和抗 CD47 抗体对 PD-L1 和 CD47 进行双重靶向，显著增强了 NK 细胞毒性以及抗肿瘤效应分子 TNF- 和 granzyme B 的分泌。这些发现支持在含 ELO 的 MM 方案中加入 CTX，并为将 POM 与免疫检查点阻断联合以最大化 NK 对 MM 的细胞毒性提供了依据。
Multiple myeloma (MM), a malignancy of plasma cells, remains largely incurable despite recent advances in treatment options. Elotuzumab (ELO) is a humanised IgG1 monoclonal antibody that targets the extracellular domain of signalling lymphocytic activation molecule F7 (SLAMF7). While ELO alone has shown modest single agent activity, combination with immunomodulatory drugs (IMIDs), such as lenalidomide and pomalidomide (POM), has proven beneficial in treating MM. However, further research is needed to find optimal combination strategies to improve efficacy. We assessed the effects of the combination of cyclophosphamide (CTX) with POM and ELO alone or in combination with novel immune checkpoint inhibitors on NK cell-mediated anti-MM effects. Tumour cell secretome (TCS) was collected from cyclophosphamide-treated ( CTX ) or pomalidomide-treated MM cells ( POM ) or a combination of both ( CTX+POM ). Primary human NK cells were conditioned with TCS CTX , TCS POM or TCS CTX+POM and NK phenotype, migration and cytotoxicity were assessed. We show that CTX alone or in combination with POM alters the tumour secretome of MM cells and promotes NK cell recruitment and anti-tumour cytotoxicity. CTX and POM treatment maintained SLAMF7 expression on MM cells and NK cells exposed to TCS CTX or CTX+POM from MM cells potentiated the effects of ELO in enhancing NK-mediated cytotoxicity. NK cells exposed to the TCS CTX or CTX+POM from MM cells potentiated NK cell cytotoxicity of MM cells and induced expression of PD-L1 and CD47 on MM cells. Dual targeting of PD-L1 and CD47 using anti-PD-1 and an anti-CD47 antibody significantly enhanced NK cytotoxicity and secretion of anti-tumour effector molecules, TNF- and granzyme B. These findings support the addition of CTX to ELO-containing MM regimens and provide a rationale for combining POM with immune checkpoint blockade to maximise NK cytotoxicity against MM.
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