Multifunctional Immunoliposomes Enhance the Immunotherapeutic Effects of PD‐L1 Antibodies against Melanoma by Reprogramming Immunosuppressive Tumor Microenvironment,Small

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Multifunctional Immunoliposomes Enhance the Immunotherapeutic Effects of PD‐L1 Antibodies against Melanoma by Reprogramming Immunosuppressive Tumor Microenvironment
Small ( IF 13.0 ) Pub Date : 2021-12-16 , DOI: 10.1002/smll.202105118
Yu Hei _{1,

2} , Yang Chen ₃ , Qian Li ₃ , Zi Mei ₁ , Jijia Pan ₃ , Siqi Zhang ₄ , Chunyang Xiong _{2,

5,

6} , Xiaodong Su ₇ , Shicheng Wei _{1,

3}

Affiliation

The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8⁺ cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the “don't eat me” signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the “do not eat me” pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.

中文翻译：

多功能免疫脂质体通过重编程免疫抑制性肿瘤微环境增强 PD-L1 抗体对黑色素瘤的免疫治疗作用

免疫抑制性肿瘤微环境 (TME) 可通过抑制 CD8 ^{+的浸润显着限制 PD-L1 抗体 (aPDL1) 的免疫治疗作用}细胞毒性 T 细胞 (CTL) 进入肿瘤组织。然而，如何重新编程免疫抑制性 TME 并促进 CTLs 的浸润仍然是 aPDL1 实现最大效益的巨大挑战。在此，作者设计了一种多功能免疫脂质体，它包裹着肾上腺素能受体阻滞剂卡维地洛 (CAR)，并通过活性氧 (ROS) 敏感的接头将“不要吃我”信号抗体 (aCD47) 和 aPDL1 串联起来。表面。在富含ROS的免疫抑制TME中，多功能免疫脂质体（CAR@aCD47/aPDL1-SSL）可以首先释放外层aCD47来阻断“不要吃我”通路，促进吞噬细胞对肿瘤细胞的吞噬作用，并激活CTLs。然后，暴露脂质体表面的aPDL1，阻断PD-1/PD-L1信号通路，从而诱导 CTL 杀死肿瘤细胞。CAR@aCD47/aPDL1-SSL 封装的 CAR 可以阻断肿瘤组织中的肾上腺素能神经并降低其密度，从而抑制肿瘤组织中的血管生成并重新编程免疫抑制性 TME。结果表明，CAR@aCD47/aPDL1-SSL 是一种重新编程免疫抑制性 TME 的有效途径，可显着提高 aPDL1 对原发性癌症和转移灶的免疫治疗效率。

更新日期：2021-12-16

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