Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer.
Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer.
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DOI：
10.1158/0008-5472.can-19-4036
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发表时间：
2020-12-01
期刊：
影响因子：
11.2
通讯作者：
Goldman A
中科院分区：
文献类型：
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作者：
Smalley M;Natarajan SK;Mondal J;Best D;Goldman D;Shanthappa B;Pellowe M;Dash C;Saha T;Khiste S;Ramadurai N;Eton EO;Smalley JL;Brown A;Thayakumar A;Rahman M;Arai K;Kohandel M;Sengupta S;Goldman A
药物引起的耐药性或耐受性是一种新兴的抗癌治疗失败，但人们对此知之甚少。耐药癌细胞与肿瘤内先天免疫之间的相互作用、对肿瘤生长的影响以及应对这些挑战的治疗策略仍未得到描述。在这里，我们阐明了紫杉烷诱导的耐药性对三阴性乳腺癌 (TNBC) 中自然杀伤 (NK) 细胞肿瘤免疫的作用，以及时空控制纳米药物的设计，可提高治疗效果并激活“残疾”的 NK。药物耐受性通过药物诱导 NK 激活配体受体轴、自然杀伤组 2 成员 D (NKG2D) 和 MHC I 类多肽相关序列 A、B (MICA/B) 的消耗来限制 NK 细胞免疫监视。经验证据支持的系统生物学表明，热休克蛋白 90 (Hsp90) 同时控制免疫监视和药物治疗肿瘤细胞的持久性。基于这一证据，我们设计了一种“嵌合”纳米治疗工具，包含紫杉烷类和胆固醇束缚的 Hsp90 抑制剂根赤霉素，它以肿瘤为目标，降低耐受性，并通过体外和体内药物释放的时间控制，延长 NK 激活配体受体的诱导，从而最佳地重新启动 NK 细胞。人类离体 TNBC 模型证实了 NK 细胞在临床批准药物压力下药物诱导的死亡中的重要性。这些发现强调了药物诱导的耐药性、肿瘤免疫背景和考虑肿瘤和微环境的工程方法之间的融合，以提高组合治疗的成功率。
Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatio-temporally controlled nanomedicines, which boost therapeutic efficacy and invigorate ‘disabled’ NK. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, natural killer group 2 member D (NKG2D) and MHC class I polypeptide-related sequence A, B (MICA/B). Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. Based on this evidence, we engineered a ‘chimeric’ nano-therapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally re-primes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically-approved agents. These findings highlight a convergence between drug-induced resistance, the tumor-immune contexture, and engineered approaches that considers the tumor and microenvironment to improve the success of combinatorial therapy.