Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China.
Biomaterials. 2022 Jun;285:121528. doi: 10.1016/j.biomaterials.2022.121528. Epub 2022 Apr 22.
Immunotherapy maintains the cancer-immunity cycle via re-activating the immune system, so as to achieve the purpose of anti-tumor. However, the response rate of current tumor immunotherapy strategies is still low. Even the most reported immune checkpoint block (ICB), the objective response rate (ORR) is only about 10-30%. Here, aiming at obtaining a higher response rate, we designed a cascade amplification nanocomposite consisting of the immune adjuvant polyinosinic:polycytidylic acid [Poly (I:C)] and aggregation-induced emission luminogen (AIEgen)-modified modular peptide (named PMRA). The PMRA includes: PPA-1 peptide (P), an immune checkpoint inhibitor; PLGLAG peptide (M), a matrix metalloproteinase 2 (MMP-2) responsive sequence to promote the release of PPA-1; RRRRRRRR peptide (R), for loading the Poly (I:C); PyTPA (A), a photosensitizer with AIE property. In cancer-immunity cycle, photodynamic therapy (PDT) mediated by PyTPA promotes the release of tumor-associated antigens (TAAs), and primes T lymphocytes. The cytokines coming from the stimulation of PDT and Poly (I:C) promote the activation of T lymphocytes. The high level of chemokines in tumor microenvironment promotes immune cells migration and infiltration in tumor with the assistance of PDT. Finally, through ICB with PPA-1 peptide, T lymphocytes enhance the recognition of tumor cells and killing tumor cells. Immunogenic cell death induces the release of more TAAs, which will enter the next cycle and complete the full-loop again. Taking advantages of whole cancer-immunity cycle, the cascade amplification nanocomposite achieved almost 100% ORR in vivo. This concept of whole cancer-immunity cycle enhanced immunotherapy provides a novel perspective for tumor treatment.
免疫疗法通过重新激活免疫系统来维持癌症免疫循环，从而达到抗肿瘤的目的。然而，目前肿瘤免疫疗法的反应率仍然较低。即使是报道最多的免疫检查点阻断（ICB），客观缓解率（ORR）也只有约 10-30%。在这里，为了获得更高的反应率，我们设计了一种级联放大纳米复合材料，由免疫佐剂聚肌苷酸：聚胞苷酸[Poly（I：C）]和聚集诱导发射发光体（AIEgen）修饰的模块化肽（命名为 PMRA）组成。PMRA 包括：PPA-1 肽（P），一种免疫检查点抑制剂；PLGLAG 肽（M），基质金属蛋白酶 2（MMP-2）响应序列，以促进 PPA-1 的释放；RRRRRRRRR 肽（R），用于加载 Poly（I：C）；PyTPA（A），一种具有 AIE 特性的光动力治疗剂。在癌症免疫循环中，PyTPA 介导的光动力治疗（PDT）促进肿瘤相关抗原（TAA）的释放，并启动 T 淋巴细胞。来自 PDT 和 Poly（I：C）刺激的细胞因子促进 T 淋巴细胞的激活。肿瘤微环境中趋化因子的高水平在 PDT 的协助下促进免疫细胞向肿瘤迁移和浸润。最后，通过 PPA-1 肽的 ICB，T 淋巴细胞增强对肿瘤细胞的识别和杀伤肿瘤细胞。免疫原性细胞死亡诱导更多 TAA 的释放，这些 TAA 将进入下一个循环并再次完成整个循环。利用整个癌症免疫循环，级联放大纳米复合材料在体内实现了近 100%的 ORR。这种基于整个癌症免疫循环的增强免疫疗法为肿瘤治疗提供了新的视角。
