Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
Acta Biomater. 2022 Nov;153:124-138. doi: 10.1016/j.actbio.2022.09.060. Epub 2022 Sep 28.
Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells, including CD4 T, CD8 T, NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. STATEMENT OF SIGNIFICANCE: Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.
血管异常与肿瘤免疫抑制微环境直接相关，这是有效免疫治疗的重要障碍。抗血管生成治疗与免疫治疗的结合可能促进免疫重编程和血管正常化的相互增强循环，从而提高免疫治疗的效果。在此，通过阿帕替尼、CD47 抗体（aCD47）和 CpG 的控制释放，使用水凝胶/纳米系统介导的抗血管生成联合免疫治疗策略来调节肿瘤微环境。水凝胶与纳米颗粒的结合保护了药物活性并维持了药物的长期缓慢释放，以实现最大的协同疗效。阿帕替尼促进肿瘤血管正常化，并增强基于 aCD47 的免疫治疗效果。添加免疫佐剂 CpG 进一步增强了抗原呈递，并刺激了巨噬细胞的抗肿瘤活性，从而增强了抗血管生成联合免疫治疗的效果。主要效应免疫细胞，包括 CD4 T、CD8 T、NK 和活性 DCs，在联合治疗后显著增加，而各种免疫抑制细胞的比例显著降低，特别是 MDSCs 和 M2 极化的巨噬细胞。基于有效的全身免疫反应，水凝胶/纳米颗粒介导的抗血管生成和免疫治疗的协同组合增强了对原发性肿瘤的协同作用，并防止了肿瘤转移。基于生物材料的抗血管生成联合免疫治疗策略是一种很有前途的有效免疫治疗策略。
缓解肿瘤微环境的免疫抑制是恢复和重建机体正常抗肿瘤免疫防御的关键。血管异常与肿瘤免疫抑制微环境直接相关，这是有效免疫治疗的重要障碍。抗血管生成与免疫治疗的结合可能促进免疫重编程和血管正常化的相互增强循环，从而提高免疫治疗的效果。对于抗血管生成和免疫治疗的结合，有效的药物输送以克服局部免疫耐受并调节肿瘤微环境以提高治疗效果是一个重要问题。水凝胶/纳米材料复合系统构建了双重持续释放系统，以实现抗血管生成药物和免疫免疫治疗药物的逐步控制释放，从而促进协同联合治疗。
