Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer.
Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer.
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在胰腺癌的3D体外异细胞模型中用三受体靶向纳米缀合物引发T细胞介导的免疫应答的光动力学引发
DOI：
10.1515/nanoph-2021-0304
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发表时间：
2021-09
期刊：
影响因子：
7.5
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中科院分区：
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光动力启动（PDP）是光动力治疗的附带效应，可以暂时改变细胞毒性区域之外的肿瘤微环境（TME）。研究表明，PDP 通过释放损伤相关分子模式和肿瘤相关抗原，诱导免疫原性细胞死亡，从而增加肿瘤通透性并调节免疫刺激效应。胰腺导管腺癌 (PDAC) 是最致命的癌症之一，具有顽固的免疫抑制性 TME 和致密的间质，对当前通常涉及大分子的分子靶向治疗提出了挑战。因此，我们测试了以下假设：PDP 的 TME 调节将实现靶向治疗并导致免疫刺激。使用三重受体靶向光免疫纳米缀合物 (TR-PINs) 介导的 PDP，靶向表皮生长因子受体、转铁蛋白受体和人表皮生长因子受体 2，我们在人 PDA C 细胞 (MIAPaCa-2) 中显示光剂量依赖性 TR-PIN 介导的细胞毒性，与人胰腺癌相关成纤维细胞 (PCAF) 在球体中共培养。此外，TR-PINs 以光剂量和时间依赖性方式诱导热休克蛋白（Hsp60、Hsp70）、钙网蛋白和高迁移率族蛋白 1 的表达。在免疫细胞与 MIA PaCa-2-PCAF 球体的共培养物中观察到 TR-PINs 介导的 T 细胞活化。 CD4+ T 和 CD8+ T 细胞在 PDP 后通过上调脱颗粒标志物 CD107a 和干扰素 γ 表现出轻剂量和时间依赖性的抗肿瘤反应性。第 3 天，免疫细胞-球体共培养物中的大量肿瘤细胞死亡，表明抗肿瘤 T 细胞激活及其识别肿瘤以进行轻度剂量依赖性杀伤的能力增强。这些数据证实了 PDP 诱导的光毒性、TME 调节和靶向纳米结构增强的免疫原性介导的异质胰腺球体的破坏增强。
Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP’s TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity inhuman PDA Ccells (MIAPaCa-2),co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner.TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs.