Communications Biology
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2024
·Vol. 7
·期 1
·1-16
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IF 5.2
Ren Huihong,Zhang Yujuan,Huang Wei,Xu Haiyan,He Weixiong,Hao Nan,Zhang Cong
Photothermal therapy (PTT) is a cancer-targeted treatment approach.The occurrence of tumors may be related to microbial infections (Viruses, bacteria, fungi, etc.), which probably provokes anti-tumor immunity. However, T cells in the context of cancer become exhausted and dysfunctional. Galectin-9 (Gal-9) is highly expressed in normal tissues and associates with body immune tolerance, and was firstly evidenced with much higher expression on the primary solid tumors than CD80/86 (B7) and CD274 (PD-L1) here, which suggests that Gal-9 may be a key factor in inhibiting the anti-tumor immunity, and its receptor T cell immunoglobulin and mucin domain 3 (TIM-3) was discovered on the cytotoxic T lymphocytes (CTL) with high expression as well based on the single cell analysis. The immune checkpoint communications showed that the Gal-9/TIM-3 axis played the most vital role on negatively regulating the anti-tumor immunity of CTL for melanoma. Then, we used a novel transdermal photothermal nanosensitizer (FSGG) loading Gal-9 siRNA (FSGG/siGal-9) for knocking the tumor cells down Gal-9 to block the Gal-9/TIM-3 axis and prohibit CTL exhaustion synergizing PTT against melanoma, which evidenced good effects on inhibiting tumor growth and enhancing anti-tumor immunity, named “photothermal immunotherapy”. This paper provides a new perspective for tumor prevention and treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Ying Huang,Jiale Li,Yingzhou Qin,Bo Qie,Qianqian Wang,Cuijuan Liu,Yimin Zhu
A cyclic peptide binding with TIM-3, TBP1, was screened by a novel CX 12 C cyclic peptide display library base on bacterial surface display. • TBP1 effectively disrupted TIM-3 interactions with CEACAM-1 and PtdSer. • TBP1 restored the function of exhausted T cells in vitro . • TBP1 synergized with anti-PD-1 antibody, improving anti-tumor immunity in vivo . Immune checkpoint blockade (ICB) therapies, particularly antibodies blocking, the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), have shown clinical success but remain limited by suboptimal response rates, often due to insufficient immune activation. T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3), a non-redundant immune checkpoint frequently co-expressed with PD-1, drives severe T-cell exhaustion in solid tumors and contributes to resistance against anti-PD-1/PD-L1 therapy. Thus, dual blockade of TIM-3 and PD-1 may restore more effective anti-tumor immunity. Compared to antibodies, low-molecular-weight peptides offer advantages in combination therapy, including better tissue penetration, lower immunogenicity, improved tolerability and low production costs. Cyclic peptides, in particular, provide enhanced biological activity and proteolytic stability. Here, we present TBP1, a cyclic peptide identified via a bacterial surface display library, which binds TIM-3 with high affinity and specificity. Competitive blocking assays and molecular docking confirmed that TBP1 effectively disrupts TIM-3 interactions with Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and Phosphatidylserine (PtdSer). In vitro , TBP1 restored exhausted T-cell function by disrupting the TIM-3/CEACAM-1 interaction. In CT26 tumor-bearing mice, TBP1 synergized with an anti-PD-1 antibody, enhancing anti-tumor immunity by promoting CD4 + T cell infiltration and IL-2 secretion. These findings identify TBP1 as a novel TIM-3-targeting cyclic peptide and support its potential application in combination immune checkpoint blockade. Download: Download high-res image (372KB) Download: Download full-size image
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DOI
高影响因子
Experimental and Therapeutic Medicine
·
2017
·Vol. 14
·期 3
·2721-2727
·
IF 1.261
Rui Wu,Li Long,Qiqi Chen,Xiaodan Wu,Jing Zhu,Bin Zhou,Jia Cheng
The objective of the present study was to investigate the effects of Tim‑3 silencing on cell viability and lipopolysaccharide (LPS)‑induced inflammatory reactions in fibroblast‑like synoviocytes (FLS). T‑cell immunoglobulin mucin domain molecule (Tim)‑3 expression in FLS obtained from patients with rheumatoid arthritis (RA) and normal controls were detected by western blot analysis and reverse transcription‑polymerase chain reaction (RT‑PCR). Small interfering (si)RNA was transfected using Lipofectamine® 2000 to decrease Tim‑3 expression. Following transfection, FLS were stimulated by LPS. An MTT assay, RT‑PCR and western blot analysis were performed to measure cell viability, Toll‑like receptor 4 (TLR4) signaling pathway‑related protein expression and inflammatory cytokine release, respectively. The results of the present study indicated that Tim‑3 expression was increased in FLS from patients with RA compared with FLS from healthy controls. Transfection of Tim‑3 siRNA significantly decreased Tim‑3 expression in FLS from patients with RA. Notably, Tim‑3 silencing decreased FLS cell viability. Following stimulation with LPS, cell viability and the expression of TLR4, myeloid differentiation protein gene 88 (MyD88) and nuclear factor‑κB (NF‑κB) p65 were enhanced in FLS. By contrast, Tim‑3 silencing attenuated LPS‑induced cell proliferation and the expression of TLR4, MyD88 and NF‑κB p65. In addition, LPS significantly increased levels of cytokines in the supernatant, including tumor necrosis factor‑α, interferon‑γ and interleukin‑6 (P<0.01). By contrast, Tim‑3 silencing significantly decreased LPS‑induced cytokine release (P<0.01). However, Tim‑3 silencing did not affect TLR4, MyD88 and NF‑κB p65 expression and the release of cytokines in cells that did not undergo treatment with LPS. Therefore, the results of the present study indicate that Tim‑3 silencing decreases the viability of FLS in RA and attenuates the LPS‑induced inflammatory reaction.
研究领域:
免疫学
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风湿病学
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细胞生物学
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炎症
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DOI
PubMed
高影响因子
Materials Today Bio
·
2022
·
IF 10.761
Chenghua Song,Jia Zhang,Ruichao Wen,Qingshan Li,Jiaxuan Zhou,Xiaoli liu,Zheng Wu,Yi Lv,Rongqian Wu
Effective systemic treatment for hepatocellular carcinoma (HCC) remains urgently needed. Sorafenib is the first FDA-approved systemic treatment for HCC. However, individual HCC patents’ response to sorafenib varies greatly. How to enhance the anti-HCC effect of sorafenib is still a significant challenge. T cell immunoglobulin mucin-3 (Tim-3) is a newly identified immune checkpoint molecule and a promising target for HCC treatment. Herein, we developed a novel pH-triggered drug-eluting nanoparticle ( [email protected] & [email protected] ) for simultaneously delivery of Tim-3 siRNA and sorafenib to HCC in situ . By a single emulsification method, a representative HCC targeted-therapeutic drug sorafenib (SF) was encapsulated into the pH-triggered positive-charged mPEG5K-PAE10K (PP) nanoparticles, followed by condensing of negative-charged Tim-3 siRNA. Then, carboxymethyl chitosan (CMCS), an amphoteric polysaccharide with negative charge in the physiological pH and positive charge in the acidic environment of the tumor, was eventually adsorbed onto the surface of nanoparticles. This co-delivery nanoparticle rapidly and specifically accumulated in the tumor site of the liver and enhanced the targeted, specific and multiple release of siRNA and sorafenib. Enhanced Tim-3 siRNA transfected into tumor cells can not only directly inhibit the growth of tumor cells by knock down the expression Tim-3, but also induce the immune response and enhance the recruitment of cytotoxic T cells to kill tumor cells. The following pH-triggered sorafenib release from [email protected] NPs greatly inhibited the tumor proliferation and angiogenesis, resulting in remarkable tumor growth inhibition in a mouse hepatoma 22 (H22) orthotopic tumor model. Thus, co-delivery of Tim-3 siRNA and sorafenib via this novel pH triggered drug-eluting nanoparticle enhances their anti-tumor efficacy. We expect that such combination treatment strategy will have great potential in future clinical applications.
研究领域:
肿瘤学
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药学
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纳米技术
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免疫治疗
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DOI
PubMed
高影响因子
Immunity Inflammation and Disease
·
2024
·Vol. 12
·期 2
·e1177
·
IF 3.1
Nannan Pang,Shabaaiti Tudahong,Yuejie Zhu,Jiang He,Chunxia Han,Gang Chen,Weiguo Wang,Jing Wang,Jianbing Ding
Background Acute graft-versus-host disease (aGVHD) arises from the imbalance of host T cells. Galectin-9 negatively regulates CD4 effector T cell (Th1 and Th17) function by binding to Tim-3. However, the relationship between Galectin-9/Tim-3 and CD4 + T subsets in patients with aGVHD after Haplo-HSCT (haploidentical peripheral blood hematopoietic stem cell transplantation) has not been fully elucidated. Here, we investigated the role of Galectin-9 and CD4 + T subsets in aGVHD after haplo-HSCT. Methods Forty-two patients underwent Haplo-HSCT (26 without aGVHD and 16 with aGVHD), and 20 healthy controls were included. The concentrations of Galectin-9, interferon-gamma (IFN-γ), interleukin (IL)-4, transforming growth factor (TGF)-β, and IL-17 in the serum and culture supernatant were measured using enzyme-linked immunosorbent assay or cytometric bead array. The expression levels of Galectin-9, PI3K, p-PI3K, and p-mTOR protein were detected by western blot analysis. Flow cytometry was used to analyze the proportions of CD4 + T cell subsets. Bioinformatics analysis was performed. Results In patients with aGVHD, regulatory T (Treg) cells and Galectin-9 decreased, and the Th1, Th17, and Treg cells were significantly imbalanced. Moreover, Treg and Galectin-9 were rapidly reconstituted in the early stage of patients without aGVHD after Haplo-HSCT, but Th17 cells were reconstituted slowly. Furthermore, Tim-3 upregulation on Th17 and Th1 cells was associated with excessive activation of the PI3K/AKT pathway in patients with aGVHD. Specifically, in vitro treatment with Galectin-9 reduced IFN-γ and IL-17 production while augmenting TGF-β secretion. Bioinformatics analysis suggested the potential involvement of the PI3K/AKT/mTOR pathway in aGVHD. Mechanistically, exogenous Galectin-9 was found to mitigate aGVHD by restoring the Treg/Teffs (effector T cells) balance and suppressing PI3K. Conclusion Galectin-9 may ameliorate aGVHD after haplo-HSCT by modulating Treg/Teffs balance and regulating the PI3K/AKT/mTOR pathway. Targeting Galectin-9 may hold potential value for the treatment of aGVHD.
研究领域:
免疫学
·
血液学
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移植学
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分子生物学
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DOI
PubMed
高影响因子
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