State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
Theranostics. 2018 Jan 1;8(3):860-873. doi: 10.7150/thno.19826. eCollection 2018.
Recently, near-infrared (NIR) light-based photothermal therapy (PTT) has been widely applied in cancer treatment. However, in most cases, the tissue penetration depth of NIR light is not sufficient and thus photothermal therapy is unable to completely eradicate deep, seated tumors inevitably leading to recurrence of the tumor. Due to this significant limitation of NIR, improved therapeutic strategies are urgently needed. We developed an endogenous vaccine based on a novel nanoparticle platform for combinatorial photothermal ablation and immunotherapy. The design was based on fluorophore-loaded liposomes (IR-7-lipo) coated with a multivalent immunoadjuvant (HA-CpG). In vitro PTT potency was assessed in cells by LIVE/DEAD and Annexin V-FITC/PI assays. The effect on bone marrow-derived dendritic cells (BMDC) maturation and antigen presentation was evaluated by flow cytometry (FCM) with specific antibodies. After treatment, the immune cell populations in tumor micro-environment and the cytokines in the serum were detected by FCM and Elisa assay, respectively. Finally, the therapeutic outcome was investigated in an animal model. Upon irradiation with 808 nm laser, IR-7-lipo induced tumor cell necrosis and released tumor-associated antigens, while the multivalent immunoadjuvant improved the expression of co-stimulatory molecules on BMDC and promoted antigen presentation. The combination therapy of PTT and immunotherapy regulated the tumor micro-environment, decreased immunosuppression, and potentiated host antitumor immunity. Most significantly, due to an enhanced antitumor immune response, combined photothermal immunotherapy was effective in eradicating tumors in mice and inhibiting tumor metastasis. This endogenous vaccination strategy based on synergistic photothermal and immunotherapy may provide a potentially effective approach for treatment of cancers, especially those difficult to be surgically removed.
近年来，近红外（NIR）光基于光热疗法（PTT）已被广泛应用于癌症治疗。然而，在大多数情况下，NIR 光的组织穿透深度不足，因此光热疗法无法完全根除深部、位于深处的肿瘤，不可避免地导致肿瘤复发。由于 NIR 的这一显著限制，迫切需要改进的治疗策略。
我们开发了一种基于新型纳米颗粒平台的内源性疫苗，用于联合光热消融和免疫治疗。该设计基于负载荧光团的脂质体（IR-7-lipo），其表面覆盖有多价免疫佐剂（HA-CpG）。通过 LIVE/DEAD 和 Annexin V-FITC/PI 测定法在细胞中评估体外 PTT 效力。通过流式细胞术（FCM）用特异性抗体评估对骨髓来源的树突状细胞（BMDC）成熟和抗原呈递的影响。治疗后，通过 FCM 和 Elisa 测定法分别检测肿瘤微环境中的免疫细胞群和血清中的细胞因子。最后，在动物模型中研究了治疗效果。
在用 808nm 激光照射时，IR-7-lipo 诱导肿瘤细胞坏死并释放肿瘤相关抗原，而多价免疫佐剂提高了 BMDC 上共刺激分子的表达，并促进了抗原呈递。PTT 和免疫治疗的联合治疗调节了肿瘤微环境，减少了免疫抑制，并增强了宿主抗肿瘤免疫。最重要的是，由于增强的抗肿瘤免疫反应，联合光热免疫治疗可有效根除小鼠肿瘤并抑制肿瘤转移。
这种基于协同光热和免疫治疗的内源性疫苗接种策略可能为癌症治疗，特别是那些难以手术切除的癌症提供一种潜在有效的方法。
