用纳米免疫丝直接体内激活 T 细胞抑制肿瘤生长和转移,ACS Nano

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用纳米免疫丝直接体内激活 T 细胞抑制肿瘤生长和转移
ACS Nano ( IF 15.8 ) Pub Date : 2023-06-20 , DOI: 10.1021/acsnano.2c11884
Lea Weiss _{1,

2,

3} , Jorieke Weiden _{1,

2,

3} , Yusuf Dölen _{1,

2} , Emilia M Grad _{1,

2} , Eric A W van Dinther _{1,

2} , Marjolein Schluck _{1,

2,

3} , Loek J Eggermont _{1,

2} , Guido van Mierlo ₄ , Uzi Gileadi ₅ , Ariadna Bartoló-Ibars ₆ , René Raavé ₇ , Mark A J Gorris _{1,

2} , Lisa Maassen ₁ , Kiek Verrijp _{1,

2} , Michael Valente _{1,

2} , Bart Deplancke ₄ , Martijn Verdoes _{1,

3} , Daniel Benitez-Ribas ₆ , Sandra Heskamp ₇ , Annemiek B van Spriel _{1,

3} , Carl G Figdor _{1,

2,

3} , Roel Hammink _{1,

2}

Affiliation

过继性 T 细胞疗法已成功应用于癌症治疗。然而，通过人工抗原呈递细胞 (aAPC) 进行的 T 细胞体外扩增仍然很麻烦，并且会损害 T 细胞的功能，从而限制其治疗潜力。我们提出了一种截然不同的方法，旨在体内直接扩增 T 细胞，从而省略大规模离体 T 细胞生产的需要。我们设计了纳米级免疫丝（IF），具有可溶性半柔性多异氰肽主链，可呈现负载肽的主要组织相容性复合物和多价共刺激分子。T 细胞的转录组分析证明，IF 很容易像天然 APC 一样激活和扩增抗原特异性 T 细胞。静脉注射后，IF 到达脾脏和淋巴结并在体内诱导抗原特异性 T 细胞反应。此外，IFs表现出强大的抗肿瘤功效，与免疫检查点阻断协同作用，抑制黑色素瘤转移的形成并减少原发性肿瘤的生长。总之，纳米级 IF 代表了一个强大的模块化平台，可用于在体内直接激活和扩增抗原特异性 T 细胞，这可以极大地促进癌症免疫治疗。

"点击查看英文标题和摘要"

Direct In Vivo Activation of T Cells with Nanosized Immunofilaments Inhibits Tumor Growth and Metastasis

Adoptive T cell therapy has successfully been implemented for the treatment of cancer. Nevertheless, ex vivo expansion of T cells by artificial antigen-presenting cells (aAPCs) remains cumbersome and can compromise T cell functionality, thereby limiting their therapeutic potential. We propose a radically different approach aimed at direct expansion of T cells in vivo, thereby omitting the need for large-scale ex vivo T cell production. We engineered nanosized immunofilaments (IFs), with a soluble semiflexible polyisocyanopeptide backbone that presents peptide-loaded major histocompatibility complexes and costimulatory molecules multivalently. IFs readily activated and expanded antigen-specific T cells like natural APCs, as evidenced by transcriptomic analyses of T cells. Upon intravenous injection, IFs reach the spleen and lymph nodes and induce antigen-specific T cell responses in vivo. Moreover, IFs display strong antitumor efficacy resulting in inhibition of the formation of melanoma metastases and reduction of primary tumor growth in synergy with immune checkpoint blockade. In conclusion, nanosized IFs represent a powerful modular platform for direct activation and expansion of antigen-specific T cells in vivo, which can greatly contribute to cancer immunotherapy.

更新日期：2023-06-20

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