ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Yuxi Gao,Jiayu Zhao,Zichao Huang,Hanqin Zhao,Zhaopei Guo,Sheng Ma,Xing Tang,Wantong Song,Xuesi Chen
OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (Treg) activity, and antagonizing inducible Treg generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing “artificial” antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.
研究领域:
免疫学
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肿瘤学
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纳米技术
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基因治疗
✓ 已验证
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
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IF 11.7
Feng Zhang,Qiuyu Jiang,Jialiang Cai,Fansheng Meng,Wenqing Tang,Zhiyong Liu,Xiahui Lin,Wenfeng Liu,Yi Zhou,Xizhong Shen,Ruyi Xue,Ling Dong,Si Zhang
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti–PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti–PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification–dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Huiyuan Zhang,Quanbin Li,Yaxing Li,Jianhua Guan,Kaidi Li,Yunlong Chen
Background: Atopic dermatitis (AD) is among the most frequently encountered skin diseases, bothering a considerable number of patients. Today, corticosteroids and antihistamines are among the numerous drugs applied for the therapy of AD. However, lengthy use of them contributes to side effects, such as physiological changes in skin. As an alternative and supplementary therapy, traditional Chinese medicine has become a trend for AD treatment. Huang-Lian-Jie-Du decoction (HLJDD), a renowned herbal formula has been employed to treat inflammatory diseases such as AD. However, its role in regulating immunity in AD remains unclear. The object of this study was to elucidate the efficacy of HLJDD and reveal the implicit mechanism from an immunological perspective in AD-like mice.Methods: In brief, 1-chloro-2,4-dinitrobenzene (DNCB) for the sensitization phase (1% DNCB) and stimulation phase (1.5% DNCB) were applied for BALB/c mice. HLJDD and dexamethasone (DXMS) were administered orally to the mice. Mice skin and spleens were collected to evaluate the efficacy of HLJDD. 16S rRNA sequencing was applied to evaluate the commensal microbiota changes in skin and fecal. In vitro, spleen CD4+ T cells and bone marrow-derived mast cells (BMMCs) were co-cultured to explore the modulation of HLJDD in T helper (Th) cells phenotyping.Results: HLJDD showcased a substantial amelioration in skin through the upregulation of FLG, LOR, AQP3, and reducing scratching behaviors in AD-like mice, Also, the quantity of infiltrated mast cells (MCs), pruritus-related mRNA were decreased. In addition, the expression of OX40/OX40L was decreased by HLJDD, which was critical in Th-cell phenotyping. With the treatment of HLJDD, Th1/Th2 and Th17/Treg ratios in AD-like mice became balanced. The structure of commensal microbiota in AD-like mice was affected by HLJDD. HLJDD could also improve the imbalance of Th17/Treg in vitro.Conclusion: HLJDD could improve the symptoms of AD-like mice by alleviating the scratching behaviors via decreased Th2 and pruritus-related mRNA expression. HLJDD also enhanced the relative diversity of skin microbiota and changed the structure of intestinal microbiota. An in-depth study found that HLJDD could balance the ratio of Th1/Th2, Th17/Treg in AD-like mice, and Th17/Treg in vitro by regulating the OX40/OX40L signaling pathway.
研究领域:
免疫学
·
皮肤病学
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中医
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
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