The biologically functional identification of a novel TIM3-binding peptide P26 in vitro and in vivo
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ORIGINAL ARTICLE
The biologically functional identification of a novel TIM3‑binding peptide P26 in vitro and in vivo Tangwu Zhong1,2 · Chuanke Zhao2 · Shuntao Wang2 · Deshuang Tao1,3 · Shuxia Ma1 · Chengchao Shou2 Received: 25 March 2020 / Accepted: 6 October 2020 © The Author(s) 2020
Abstract Purpose 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 TIM3targeting peptide screened from the phage peptide library. Methods 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. Results 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. Conclusions 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. Keywords P26 · TIM3 · Phage display peptide library · Biological activity · Anti-tumor
Introduction Immunotherapy is increasingly recognized as one of the most promising treatments for cancer therapy, and there has been a focus on the development of treatments aiming at some immunological checkpoint molecules such as anticytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) * Shuxia Ma [email protected] * Chengchao Shou [email protected] 1
School of Basic Medicine, Jiamusi University, 258 Xuefu Street, Jiamusi 154007, Heilongjiang Province, China
2
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
3
Jiamusi Central Hospital, Jiamusi 154002, Heilongjiang Province, China
and PD-1 in melanoma, kidney cancer, Hodgkin’s disease, and lung cancer [1]. However, tumors grow in the complex networks consisting of epithelial cells, blood vessels and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells [2]. In some cancers including colorectal cancer, the blockade of CTLA-4 or PD-1 does not achieve an ideal therapeutic effect and incentivizes the efforts to locate other immune checkpoint inhibitors, such as TIM3. Recent
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