Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer.
Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer.
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DOI：
10.1186/s12885-022-09612-2
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发表时间：
2022-05-06
期刊：
影响因子：
3.8
通讯作者：
Yull, Fiona E.
中科院分区：
文献类型：
--
作者：
Glass, Evan B.;Hoover, Alyssa A.;Bullock, Kennady K.;Madden, Matthew Z.;Reinfeld, Bradley, I;Harris, Whitney;Parker, Dominique;Hufnagel, Demetra H.;Crispens, Marta A.;Khabele, Dineo;Rathmell, W. Kimryn;Rathmell, Jeffrey C.;Wilson, Andrew J.;Giorgio, Todd D.;Yull, Fiona E.
目前的癌症免疫疗法已经产生了巨大的影响，但通常缺乏高反应率，特别是在卵巢癌中。需要新的疗法来提供更多的益处。一种未充分研究的方法是靶向大量免疫抑制性肿瘤相关巨噬细胞（TAM）。我们最近报道，使用可诱导的转基因小鼠，上调TAM中的核因子-κ B（NF-κB）信号传导促进M1、抗肿瘤表型并限制卵巢癌进展。我们还开发了甘露糖修饰的聚合物纳米颗粒系统（MnNP），以在体外优先将siRNA有效载荷递送至M2（促肿瘤巨噬细胞）。在这项研究中，我们使用卵巢癌小鼠模型测试了通过负载有靶向NF-κB α（IκBα）抑制剂的siRNA的MnNPs来逆转卵巢TAM的翻译策略。我们在同基因卵巢癌模型中评估了负载有IκBα siRNA（IκBα-MnNPs）或乱序siRNA的MnNPs的治疗。C57 B1/6小鼠中的ID 8肿瘤用于评估晚期疾病的召集日治疗，而FVB小鼠中的TBR 5肿瘤用于评估快速发展疾病模型中的重复治疗。在两种模型中评价MnNP的生物分布和治疗功效。使用培养的转移酶报告巨噬细胞证实了IκBα-MnNP处理对NF-κB活性的刺激和对M1表型的复极化。在两种肿瘤模型中证实了具有荧光有效负载的MnNP（Cy 5-MnNP）向实体瘤和腹水中的巨噬细胞的递送。在ID 8模型中，IκBα-MnNP的三个召唤日处理证实了体内向M1巨噬细胞极化的转变。在TBR 5模型中，在2-3周内每两周治疗一次观察到明显的治疗效果，其中显著降低的肿瘤负荷伴随着免疫细胞组成的变化，表明免疫抑制性肿瘤微环境降低。在任一模型中均未观察到与MnNP治疗相关的毒性证据。在卵巢癌小鼠模型中，MnNPs优先与腹水和实体瘤中的巨噬细胞相关。IκBα-MnNP处理小鼠中巨噬细胞复极化、炎症信号增加和肿瘤负荷减轻的证据表明，在已建立的疾病模型中取得了有益的结果。我们已经提供了一种靶向的、TAM导向的方法来增加卵巢癌的抗肿瘤免疫力的证据，这种方法具有很强的转化潜力，可用于未来的临床研究。在线版本包含补充材料，可通过10.1186/s12885-022-09612-2获得。
Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded with siRNA targeting the inhibitor of NF-κB alpha (IκBα) using mouse models of ovarian cancer. We evaluated treatment with MnNPs loaded with IκBα siRNA (IκBα-MnNPs) or scrambled siRNA in syngeneic ovarian cancer models. ID8 tumors in C57Bl/6 mice were used to evaluate consecutive-day treatment of late-stage disease while TBR5 tumors in FVB mice were used to evaluate repetitive treatments in a faster-developing disease model. MnNPs were evaluated for biodistribution and therapeutic efficacy in both models. Stimulation of NF-κB activity and repolarization to an M1 phenotype via IκBα-MnNP treatment was confirmed using cultured luciferase-reporter macrophages. Delivery of MnNPs with fluorescent payloads (Cy5-MnNPs) to macrophages in the solid tumors and ascites was confirmed in both tumor models. A three consecutive-day treatment of IκBα-MnNPs in the ID8 model validated a shift towards M1 macrophage polarization in vivo. A clear therapeutic effect was observed with biweekly treatments over 2-3 weeks in the TBR5 model where significantly reduced tumor burden was accompanied by changes in immune cell composition, indicative of reduced immunosuppressive tumor microenvironment. No evidence of toxicity associated with MnNP treatment was observed in either model. In mouse models of ovarian cancer, MnNPs were preferentially associated with macrophages in ascites fluid and solid tumors. Evidence of macrophage repolarization, increased inflammatory cues, and reduced tumor burden in IκBα-MnNP-treated mice indicate beneficial outcomes in models of established disease. We have provided evidence of a targeted, TAM-directed approach to increase anti-tumor immunity in ovarian cancer with strong translational potential for future clinical studies. The online version contains supplementary material available at 10.1186/s12885-022-09612-2.
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影响因子：
10.9
作者：
Gong J;Chehrazi-Raffle A;Reddi S;Salgia R
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Salgia R
DOI：
10.1038/nrc2644
发表时间：
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期刊：
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影响因子：
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影响因子：
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影响因子：
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作者：
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通讯作者：
Stiff PJ