Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies
Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies
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操纵 TAM 功能以促进免疫检查点抗体的免疫治疗效果
DOI：
10.1016/j.jconrel.2021.07.009
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发表时间：
2021-07-13
影响因子：
10.8
通讯作者：
Zhang, Na
中科院分区：
文献类型：
--
作者：
Liu, Yang;Liang, Shuang;Zhang, Na
免疫检查点抗体已成为新的治疗方法，而许多患者是难治性的。研究人员已经确定肿瘤相关巨噬细胞（TAMs）是参与免疫抵抗的关键因素，操纵TAMs功能将有效地改善免疫治疗。NF-κ B B通路是TAMs调控的主要调控因子之一。抑制NF-κ B通路可使M2 TAMs复极，并下调TAMs上程序性细胞死亡蛋白1（PD-1）配体1（PD-L1）的表达，从而提高免疫治疗效果。在此，将NF-κ B途径的抑制剂IMD-0354装载在甘露糖修饰的脂质纳米颗粒（M-IMD-LNP）中。然后，将PD-1抗体和M-IMD-LNP共载于基质金属蛋白酶2（MMP 2）响应性和肿瘤靶向纳米凝胶（P/ML-NNG）中。P/ML-NNG可将药物共递送至肿瘤部位，并被MMP 2降解，向不同靶点释放药物。PD-1表达、NF-κ B通路抑制、M2 TAMs上PD-L1表达和M2 TAMs复极化的评价表明P/ML-NNG可同时阻断PD-1/PD-L1和NF-κ B通路。通过对CD 4（+）T细胞、CD 8（+）T细胞、T淋巴细胞、细胞因子和抗肿瘤免疫的评价，证实IMD-0354能有效地提高免疫治疗效果。这些结果为肿瘤的免疫治疗提供了有力的参考。
Immune checkpoint antibodies have emerged as novel therapeutics, while many patients are refractory. Researchers had identified tumor-associated macrophages (TAMs) is the pivotal factor involved in immune resistance and that manipulation of TAMs functions would improve the immunotherapies effectively. NF-kappa B pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-kappa B pathway could achieve both repolarization M2 TAMs and downregulation the expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1) on TAMs to improve the effect of immunotherapies. Here, IMD-0354, inhibitor of NF-kappa B pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were coloaded in matrix metalloproteinase 2 (MMP2) responsive and tumor target nanogels (P/ML-NNG). P/ML-NNG could co-deliver drugs to tumor site, disintegrated by MMP2 and release drugs to different targets. Evaluation of PD-1 expression, inhibition of NF-kappa B pathway, expression of PD-L1 on M2 TAMs and M2 TAMs re-polarization demonstrated that P/ML-NNG could block the PD-1/PD-L1 and NF-kappa B pathways simultaneously. Evaluation of CD4 (+) T cells, CD8 (+) T cells, Tregs, cytokines and antitumor immunity confirmed that IMD-0354 could improve the immunotherapies effectively. Those results provided forceful references for tumor immunetherapy.