肿瘤细胞治疗研究
英文原题：Overcoming resistance in CD44-overexpressing myeloma through combination therapy with ATRA, bortezomib, and NK cells.
Overcoming resistance in CD44-overexpressing myeloma through combination therapy with ATRA, bortezomib, and NK cells.
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CD44 是一种细胞表面糖蛋白，在多种癌症中常过表达并与不良预后相关。本研究评估 CD44 过表达对多发性骨髓瘤（MM）的预后意义，并考察自然杀伤（NK）细胞疗法联合全反式维甲酸（ATRA）和硼替佐米（Bor）对 CD44 高表达 MM 的治疗效果。研究利用 CoMMpass 数据库临床资料，分析 CD44 表达与生存结局的关系。研究者采用 K562-OX40L-mbIL-18/21 饲养细胞并补充 IL-2 和 IL-15，从健康供者扩增 NK 细胞。功能实验使用 CD44 高表达骨髓瘤细胞系，给予 ATRA、Bor 单药或与 NK 细胞联合处理。通过静脉注射 U266-GFP-萤火虫荧光素酶细胞建立 NOD/SCID IL-2R 缺失小鼠异种移植模型，根据肿瘤生长、全身播散和生存评估疗效。
临床数据表明，在修订版国际分期系统的 I、II、III 期患者中，CD44 过表达均与总生存期较差相关（P<0.0001）。体外联合使用 ATRA 和 Bor 可下调 β-catenin 和 CD44 表达，抑制增殖、迁移和侵袭，并通过上调 MICA/B、Fas、TRAIL-R2 和细胞间黏附分子-1，增强 NK 细胞介导的细胞毒作用。体内联合 NK 细胞、ATRA 和 Bor 可显著抑制 CD44 表达、减少髓外播散并延长生存，且未见明显毒性。这些临床前发现支持 CD44 过表达是 MM 生存较差的相关标志，并为使用 ATRA 和硼替佐米进行药物预处理、增强 NK 细胞介导细胞毒性提供依据。
不过，在推断临床疗效前，该治疗策略仍需在异质性患者来源模型和前瞻性临床研究中进一步验证。
CD44 is a cell-surface glycoprotein frequently overexpressed in cancers and associated with poor prognosis.
We evaluated the prognostic significance of CD44 overexpression in multiple myeloma (MM) and investigated the therapeutic efficacy of combining natural killer (NK) cell therapy with all-trans retinoic acid (ATRA) and bortezomib (Bor) against CD44-overexpressing MM. Clinical data from the CoMMpass database were analyzed to assess survival outcomes relative to CD44 expression. NK cells were expanded from healthy donors using K562-OX40L-mbIL-18/21 feeder cells supplemented with interleukin (IL)-2 and IL-15. Functional assays were performed using CD44-high myeloma cell lines treated with ATRA and Bor, individually or in combination with NK cells. Therapeutic efficacy was evaluated based on tumor growth, systemic dissemination, and survival in an intravenous U266-green fluorescent protein-firefly luciferase xenograft NOD/SCID IL-2R null mouse model.
Clinical data showed CD44 overexpression correlated with inferior overall survival (P < 0. 0001) in all three stages I, II, and III of the revised International Stage System. In vitro, ATRA and Bor co-treatment downregulated -catenin and CD44 expression, inhibited proliferation, migration, and invasion, and enhanced NK cell-mediated cytotoxicity via upregulation of MICA/B, Fas, TRAIL-R2, and intercellular adhesion molecule-1.
In vivo, combination therapy with NK cells, ATRA, and Bor significantly suppressed CD44 expression, reduced extramedullary spread, and prolonged survival without notable toxicity. These preclinical findings support CD44 overexpression as a marker associated with inferior survival in MM and provide a rationale for pharmacologic tumor priming with ATRA and bortezomib to enhance NK cell-mediated cytotoxicity.
However, the therapeutic strategy requires further validation in heterogeneous patient-derived models and prospective clinical studies before clinical efficacy can be inferred.
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