School of Basic Medicine, Jiamusi University, 258 Xuefu Street, Jiamusi, 154007, Heilongjiang Province, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
Cancer Chemother Pharmacol. 2020 Dec;86(6):783-792. doi: 10.1007/s00280-020-04167-0. Epub 2020 Oct 21.
Recent studies have shown that TIM3 plays an important role in T-cell failure, which is closely related to the resistance to anti-programmed cell death protein 1 (PD-1) treatment. However, there have been no reports on the application of peptide blockers to TIM3. In this study, we endeavored to identify the in vitro and in vivo anti-tumor activities of a TIM3-targeting peptide screened from the phage peptide library.
Phage display peptide library technology, surface plasmon resonance, flow cytometry, and mixed lymphocyte reaction were utilized to screen and demonstrate the bioactivities of P26, a TIM3-targeting peptide. Meanwhile, tumor growth assay was performed to evaluate the anti-tumor effect of P26.
In terms of affinity, we demonstrated that P26 specifically binds to TIM3 at the cellular and molecular levels, which therefore blocks the interaction between TIM3 and Galectin-9 (Gal-9) and competes with Gal-9 to bind TIM3. Additionally, P26 significantly increases T-cell activity and elevates IFN-γ and IL-2 levels in a dose-dependent manner. Notably, P26 also counteracts Gal-9-mediated T-cell suppression. More importantly, P26 can inhibit growth of MC38-hPD-L1 tumor in mice.
P26, as a novel TIM3-binding peptide, has the ideal bioactivity connecting to TIM3 and the potential prospect of application in immunotherapy as an alternative or adjuvant to existing agents.
最近的研究表明 TIM3 在 T 细胞衰竭中发挥重要作用，这与抗程序性细胞死亡蛋白 1（PD-1）治疗的耐药性密切相关。然而，目前尚无关于肽阻滞剂应用于 TIM3 的报道。本研究旨在从噬菌体肽文库中筛选出一种针对 TIM3 的肽，研究其在体外和体内的抗肿瘤活性。
利用噬菌体展示肽库技术、表面等离子体共振、流式细胞术和混合淋巴细胞反应筛选和证明 TIM3 靶向肽 P26 的生物活性。同时，进行肿瘤生长测定以评估 P26 的抗肿瘤作用。
在亲和力方面，我们证明 P26 特异性地在细胞和分子水平上与 TIM3 结合，从而阻断 TIM3 与半乳糖凝集素-9（Gal-9）的相互作用，并与 Gal-9 竞争与 TIM3 结合。此外，P26 还能显著增加 T 细胞活性，并呈剂量依赖性提高 IFN-γ 和 IL-2 水平。值得注意的是，P26 还能拮抗 Gal-9 介导的 T 细胞抑制。更为重要的是，P26 可以抑制 MC38-hPD-L1 肿瘤在小鼠体内的生长。
P26 作为一种新型 TIM3 结合肽，具有与 TIM3 理想的结合活性，有望作为现有药物的替代或辅助物，应用于免疫治疗。
