Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes.
Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes.
复制标题
基于M2样肿瘤相关巨噬细胞靶向纳米复合体的肿瘤微环境重塑和肿瘤治疗。
作者：
Han S;Wang W;Wang S;Yang T;Zhang G;Wang D;Ju R;Lu Y;Wang H;Wang L
背景：在肿瘤微环境中的众多免疫抑制细胞中，众所周知，肿瘤相关巨噬细胞（TAM）有助于肿瘤的发展。 TAM 可以被调节（极化）以在经典 M1 样巨噬细胞或 M2 样巨噬细胞之间转变。两者都受到微环境中信号分子的调节。 M1 样 TAM 可以分泌经典的炎症细胞因子，通过促进肿瘤细胞坏死和免疫细胞浸润到肿瘤微环境来杀死肿瘤。相比之下，M2样TAM表现出强大的促肿瘤功能，包括降解肿瘤细胞外基质、破坏基底膜、促进血管生成和招募免疫抑制细胞，所有这些都进一步促进肿瘤进展和远端转移。因此，通过逆转TAM表型来重塑肿瘤微环境将有利于肿瘤治疗，尤其是免疫治疗。方法：采用超声双乳化技术制备包裹黄芩苷和黑色素瘤抗原Hgp肽片段25-33的PLGA纳米粒。纳米颗粒进一步负载 CpG 片段，并在其表面使用缀合的 M2pep 和 α-pep 肽来产生新型纳米复合物。通过流式细胞术和共聚焦显微镜在体外评估了纳米复合物靶向 M2 样 TAM 的能力和抗肿瘤免疫治疗效果。我们还研究了使用不同纳米复合物的小鼠黑色素瘤模型的存活率和组织病理学。还评估了荷黑素瘤小鼠免疫攻击的肿瘤微环境的改善。结果：纳米复合物在体外和体内均被类M2 TAM有效摄取，酸性溶酶体环境引发聚多巴胺从纳米颗粒表面崩解，从而导致有效负载的释放。释放的CpG在将M2样TAM转化为M1样表型并进一步分泌炎症细胞因子方面发挥了重要作用。 TAM 的逆转释放细胞因子并逐渐抑制肿瘤血管生成，从而重塑肿瘤微环境。此外，激活的TAM还向T细胞呈递抗原，进一步刺激抗肿瘤免疫反应，抑制肿瘤转移。激活的T细胞释放细胞因子，刺激NK细胞浸润，直接导致肿瘤细胞死亡。 M1 样 TAM 释放的黄芩苷也能杀死肿瘤细胞。结论：纳米复合物促进黄芩苷、抗原和免疫刺激剂递送至M2样TAM，从而极化和逆转M2样TAM表型并重塑肿瘤微环境以杀死肿瘤细胞。
Background: Among the many immunosuppressive cells in the tumor microenvironment, tumor-associated-macrophages (TAMs) are well known to contribute to tumor development. TAMs can be conditioned (polarized) to transition between classical M1-like macrophages, or alternatively to M2-like macrophages. Both are regulated by signaling molecules in the microenvironment. M1-like TAMs can secrete classic inflammatory cytokines that kill tumors by promoting tumor cell necrosis and immune cell infiltration into the tumor microenvironment. In contrast, M2-like TAMs exhibit powerful tumor-promoting functions, including degradation of tumor extracellular matrix, destruction of basement membrane, promotion of angiogenesis, and recruitment of immunosuppressor cells, all of which further promote tumor progression and distal metastasis. Therefore, remodeling the tumor microenvironment by reversing the TAM phenotype will be favorable for tumor therapy, especially immunotherapy. Methods: PLGA nanoparticles encapsulating baicalin and melanoma antigen Hgp peptide fragment 25-33 were fabricated using the ultrasonic double-emulsion technique. The nanoparticles were further loaded with CpG fragments and used conjugated M2pep and α-pep peptides on their surfaces to produce novel nano-complexes. The capability to target M2-like TAMs and anti-tumor immunotherapy effects of nano-complexes were evaluated by flow cytometry and confocal microscopy in vitro. We also investigated the survival and histopathology of murine melanoma models administrated with different nanocomplexes. Improvements in the tumor microenvironment for immune attack of melanoma-bearing mice were also assessed. Results: The nano-complexes were effectively ingested by M2-like TAMs in vitro and in vivo, and the acidic lysosomal environment triggered the disintegration of polydopamine from the nanoparticle surface, which resulted in the release of the payloads. The released CpG played an important role in transforming the M2-like TAMs into the M1-like phenotype that further secreted inflammatory cytokines. The reversal of TAM released cytokines and gradually suppressed tumor angiogenesis, permitting the remodeling of the tumor microenvironment. Moreover, the activated TAMs also presented antigen to T cells, which further stimulated the antitumor immune response that inhibited tumor metastasis. Activated T cells released cytokines, which stimulated NK cell infiltration and directly resulted in killing tumor cells. The baicalin released by M1-like TAMs also killed tumor cells. Conclusion: The nano-complexes facilitated baicalin, antigen, and immunostimulant delivery to M2-like TAMs, which polarized and reversed the M2-like TAM phenotype and remodeled the tumor microenvironment to allow killing of tumor cells.