Engineered Three-Dimensional Tumor Models to Study Natural Killer Cell Suppression,ACS Biomaterials Science & Engineering

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Engineered Three-Dimensional Tumor Models to Study Natural Killer Cell Suppression
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-05-26 , DOI: 10.1021/acsbiomaterials.0c00259
Madison N. Temples ₁ , Isaac M. Adjei ₁ , Phoebe M. Nimocks ₁ , Julie Djeu ₂ , Blanka Sharma ₁

Affiliation

A critical hurdle associated with natural killer (NK) cell immunotherapies is inadequate infiltration and function in the solid tumor microenvironment. Well-controlled 3D culture systems could advance our understanding of the role of various biophysical and biochemical cues that impact NK cell migration in solid tumors. The objectives of this study were to establish a biomaterial which (i) supports NK cell migration and (ii) recapitulates features of the in vivo solid tumor microenvironment, to study NK infiltration and function in a 3D system. Using peptide-functionalized poly(ethylene glycol)-based hydrogels, the extent of NK-92 cell migration was observed to be largely dependent on the density of integrin binding sites and the presence of matrix metalloproteinase degradable sites. When lung cancer cells were encapsulated into the hydrogels to create tumor microenvironments, the extent of NK-92 cell migration and functional activity was dependent on the cancer cell type and duration of 3D culture. NK-92 cells showed greater migration into the models consisting of nonmetastatic A549 cells relative to metastatic H1299 cells, and reduced migration in both models when cancer cells were cultured for 7 days versus 1 day. In addition, the production of NK cell-related pro-inflammatory cytokines and chemokines was reduced in H1299 models relative to A549 models. These differences in NK-92 cell migration and cytokine/chemokine production corresponded to differences in the production of various immunomodulatory molecules by the different cancer cells, namely, the H1299 models showed increased stress ligand shedding and immunosuppressive cytokine production, particularly TGF-β. Indeed, inhibition of TGF-β receptor I in NK-92 cells restored their infiltration in H1299 models to levels similar to that in A549 models and increased overall infiltration in both models. Relative to conventional 2D cocultures, NK-92 cell mediated cytotoxicity was reduced in the 3D tumor models, suggesting the hydrogel serves to mimic some features of the biophysical barriers in in vivo tumor microenvironments. This study demonstrates the feasibility of a synthetic hydrogel system for investigating the biophysical and biochemical cues impacting NK cell infiltration and NK cell–cancer cell interactions in the solid tumor microenvironment.

中文翻译：

工程化的三维肿瘤模型用于研究自然杀伤细胞的抑制

与自然杀伤（NK）细胞免疫疗法相关的一个关键障碍是实体瘤微环境中的浸润和功能不足。受到良好控制的3D培养系统可以使我们进一步了解影响实体瘤中NK细胞迁移的各种生物物理和生化线索的作用。这项研究的目的是建立一种生物材料，该材料（i）支持NK细胞迁移，并（ii）概括体内实体瘤微环境的特征，以研究NK在3D系统中的浸润和功能。使用基于肽功能化的聚乙二醇的水凝胶，观察到NK-92细胞迁移的程度在很大程度上取决于整联蛋白结合位点的密度和基质金属蛋白酶可降解位点的存在。当将肺癌细胞封装到水凝胶中以创建肿瘤微环境时，NK-92细胞迁移的程度和功能活性取决于癌细胞的类型和3D培养的持续时间。相对于转移性H1299细胞，NK-92细胞向由非转移性A549细胞组成的模型显示出更大的迁移，并且当癌细胞培养7天比1天时，两种模型中的迁移均减少。另外，相对于A549模型，H1299模型中NK细胞相关促炎细胞因子和趋化因子的产生减少。NK-92细胞迁移和细胞因子/趋化因子产生的这些差异对应于不同癌细胞产生的各种免疫调节分子产生的差异，即 H1299模型显示出增加的应力配体脱落和免疫抑制细胞因子的产生，特别是TGF-β。实际上，NK-92细胞中TGF-β受体I的抑制将其在H1299模型中的浸润恢复到与A549模型相似的水平，并在两个模型中均增加了总浸润。相对于常规2D共培养，在3D肿瘤模型中NK-92细胞介导的细胞毒性降低，表明水凝胶可模拟体内肿瘤微环境中的生物物理屏障的某些特征。这项研究证明了合成水凝胶系统在实体瘤微环境中研究影响NK细胞浸润和NK细胞与癌细胞相互作用的生物物理和生化线索的可行性。NK-92细胞中TGF-β受体I的抑制将其在H1299模型中的浸润恢复到与A549模型相似的水平，并在两个模型中均增加了总浸润。相对于常规2D共培养，在3D肿瘤模型中NK-92细胞介导的细胞毒性降低，表明水凝胶可模拟体内肿瘤微环境中的生物物理屏障的某些特征。这项研究证明了合成水凝胶系统在实体瘤微环境中研究影响NK细胞浸润和NK细胞与癌细胞相互作用的生物物理和生化线索的可行性。NK-92细胞中TGF-β受体I的抑制将其在H1299模型中的浸润恢复到与A549模型相似的水平，并在两个模型中均增加了总浸润。相对于常规2D共培养，在3D肿瘤模型中NK-92细胞介导的细胞毒性降低，表明水凝胶可模拟体内肿瘤微环境中的生物物理屏障的某些特征。这项研究证明了合成水凝胶系统在实体瘤微环境中研究影响NK细胞浸润和NK细胞与癌细胞相互作用的生物物理和生化线索的可行性。NK-92细胞介导的细胞毒性在3D肿瘤模型中降低，表明水凝胶可模拟体内肿瘤微环境中生物物理屏障的某些特征。这项研究证明了合成水凝胶系统在实体瘤微环境中研究影响NK细胞浸润和NK细胞与癌细胞相互作用的生物物理和生化线索的可行性。NK-92细胞介导的细胞毒性在3D肿瘤模型中降低，表明水凝胶可模拟体内肿瘤微环境中生物物理屏障的某些特征。这项研究证明了合成水凝胶系统在实体瘤微环境中研究影响NK细胞浸润和NK细胞与癌细胞相互作用的生物物理和生化线索的可行性。

更新日期：2020-07-13

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