Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, MA, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Nat Biomed Eng. 2024 May;8(5):579-592. doi: 10.1038/s41551-024-01180-z. Epub 2024 Feb 29.
Tumour-associated neutrophils can exert antitumour effects but can also assume a pro-tumoural phenotype in the immunosuppressive tumour microenvironment. Here we show that neutrophils can be polarized towards the antitumour phenotype by discoidal polymer micrometric 'patches' that adhere to the neutrophils' surfaces without being internalized. Intravenously administered micropatch-loaded neutrophils accumulated in the spleen and in tumour-draining lymph nodes, and activated splenic natural killer cells and T cells, increasing the accumulation of dendritic cells and natural killer cells. In mice bearing subcutaneous B16F10 tumours or orthotopic 4T1 tumours, intravenous injection of the micropatch-loaded neutrophils led to robust systemic immune responses, a reduction in tumour burden and improvements in survival rates. Micropatch-activated neutrophils combined with the checkpoint inhibitor anti-cytotoxic T-lymphocyte-associated protein 4 resulted in strong inhibition of the growth of B16F10 tumours, and in complete tumour regression in one-third of the treated mice. Micropatch-loaded neutrophils could provide a potent, scalable and drug-free approach for neutrophil-based cancer immunotherapy.
肿瘤相关中性粒细胞可以发挥抗肿瘤作用，但在免疫抑制性肿瘤微环境中也可以表现出促肿瘤表型。在这里，我们表明，通过圆盘状聚合物微尺寸“补丁”可以将中性粒细胞向抗肿瘤表型极化，这些“补丁”附着在中性粒细胞表面而不被内化。静脉内给予负载微补丁的中性粒细胞在脾脏和肿瘤引流淋巴结中积累，并激活脾脏自然杀伤细胞和 T 细胞，增加树突状细胞和自然杀伤细胞的积累。在皮下 B16F10 肿瘤或原位 4T1 肿瘤的小鼠中，静脉注射负载微补丁的中性粒细胞导致强烈的全身免疫反应，肿瘤负担减少，生存率提高。微补丁激活的中性粒细胞与检查点抑制剂抗细胞毒性 T 淋巴细胞相关蛋白 4 结合，导致 B16F10 肿瘤的强烈抑制，并使三分之一接受治疗的小鼠完全消退肿瘤。负载微补丁的中性粒细胞可为基于中性粒细胞的癌症免疫治疗提供一种有效、可扩展且无药物的方法。
