Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China; Key Laboratory for Nanomedicine, Department of Histology and Embryology and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, PR China.
Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China.
Biomaterials. 2022 Feb;281:121341. doi: 10.1016/j.biomaterials.2021.121341. Epub 2021 Dec 29.
Although chimeric antigen receptor T (CAR T) cell immunotherapy has demonstrated remarkable success in clinical, therapeutic effects are still limited in solid tumor due to lack of activated T cell infiltration in immunosuppression of tumor microenvironment. Herein, we develop IL-12 nanostimulant-engineered CAR T cell (INS-CAR T) biohybrids for boosting antitumor immunity of CAR T cells via immunofeedback. As stimulating nanochaperone, IL-12-loaded human serum albumin (HSA) nanoparticles are effectively conjugated onto CAR T cells via bioorthogonal chemistry without influencing their antitumor capabilities. IL-12 is responsively released from INS-CAR T biohybrids in presence of the increased thiol groups on cell-surface triggered by tumor antigens. In return, released IL-12 obviously promotes the secretion of CCL5, CCL2 and CXCL10, which further selectively recruits and expands CD8 CAR T cells in tumors. Ultimately, the immune-enhancing effects of IL-12 nanochaperone significantly boost CAR T cell antitumor capabilities, dramatically eliminated solid tumor and minimized unwanted side effects. Hence, immunofeedback INS-CAR T biohybrids, which include INS that serves as an intelligent 'nanochaperone', could provide a powerful tool for efficient and safe antitumor immunotherapy.
尽管嵌合抗原受体 T（CAR T）细胞免疫疗法在临床中已显示出显著的成功，但由于肿瘤微环境中的免疫抑制导致激活的 T 细胞浸润不足，其治疗效果在实体瘤中仍然有限。在此，我们通过免疫反馈开发了白细胞介素 12 纳米佐剂工程化 CAR T 细胞（INS-CAR T）生物杂种，以增强 CAR T 细胞的抗肿瘤免疫。作为刺激纳米载体，负载白细胞介素 12 的人血清白蛋白（HSA）纳米颗粒通过生物正交化学有效地被共轭到 CAR T 细胞上，而不影响其抗肿瘤能力。在肿瘤抗原触发的细胞表面增加的巯基存在下，INS-CAR T 生物杂种中负载的白细胞介素 12 会被响应性释放。反过来，释放的白细胞介素 12 明显促进 CCL5、CCL2 和 CXCL10 的分泌，这进一步选择性地募集和扩增肿瘤中的 CD8 CAR T 细胞。最终，白细胞介素 12 纳米载体的免疫增强作用显著增强了 CAR T 细胞的抗肿瘤能力，显著消除了实体瘤并最小化了不必要的副作用。因此，作为智能“纳米载体”的免疫反馈 INS-CAR T 生物杂种为高效和安全的抗肿瘤免疫疗法提供了有力的工具。
