IMMUNITY
·
2024
·
IF 25.5
Rui Ding,Xiaoyan Yu,Zhilin Hu,Yu Dong,Haiyan Huang,Yuerong Zhang,Qiaoqiao Han,Zhi-Yu Ni,Ren Zhao,Youqiong Ye,Qiang Zou
RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.
研究领域:
免疫学
·
肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Extracellular Vesicles
·
2025
·Vol. 14
·期 4
·e70068
·
IF 14.5
Jiangbin Chen,Qi Tan,Zimo Yang,Wenjuan Chen,E. Zhou,Minglei Li,Jingjing Deng,Yali Wu,Jiatong Liu,Juanjuan Xu,Mengfei Guo,Yang Jin
Dendritic cell (DC)-derived extracellular vesicles (DEVs) are promising candidates for cancer vaccines, but their therapeutic effects still need further optimization. In this study, we utilized neoantigens, lipopolysaccharide and IFN-γ to induce the maturation of DCs, and then isolated DEVs derived from these mature DCs. We showed that the immune checkpoint inhibitor (anti-CTLA-4 antibody, aCTLA-4) can improve the immunostimulatory function of DEVs by directly activating T cells through immune checkpoint signal blockade. The cytokine interleukin-12 (IL-12), as one of the third signals for T cell activation, can also enhance the capability of DEVs to activate T cells directly. Based on these findings, we designed the engineered DEVs conjugated with IL-12 and aCTLA-4 (DEV@IL-12-aCTLA-4) to improve the therapeutic potential of DEVs by providing sufficient immune regulatory signals. Moreover, the carrier property of DEVs also contributes to the delivery of IL-12 and aCTLA-4 to lymph nodes. This indicates that the conjugation of DEVs with IL-12 and aCTLA-4 constitutes a complementary approach, where IL-12 and aCTLA-4 help to enhance the T cell activation effect of DEVs, and DEVs facilitate the delivery of IL-12 and aCTLA-4. Our results showed that DEV@IL-12-aCTLA-4 can enhance the Th1 immune response and reverse exhausted CD8 + T cells in the tumour microenvironment, effectively inducing robust T cell immune responses and inhibiting tumour growth in tumour-bearing mice. Overall, this study expands the theoretical foundation of DEVs and provides a universal strategy for optimizing cancer combination immunotherapy by reprogramming DEVs.
研究领域:
免疫学
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 17
·4757-4766
·
IF 6.183
Jing Zhang,Dan Liu,Jiale Liu,Yanfeng Han,Haiyan Xu,Xigang Leng,Deling Kong,Lanxia Liu
Combined blockades of CTLA-4 and PD-1 can yield better overall complementary clinical outcomes than individual blockades, but the response rates are still relatively low. To investigate the anti-tumor effects of various combined strategies, we designed various spherical nucleotide nanoparticles (SNPs) loaded with CTLA-4 aptamer (cSNPs), PD-1 siRNA (pSNPs) or both (hybrid SNPs, or hSNPs). The results demonstrated that hSNPs could promote significantly stronger anti-tumor immune responses in a nonredundant fashion than the mixture of pSNPs and cSNPs (pSNPs & cSNPs). We reasoned that this is because all individual immune cells could receive both CTLA-4 and PD-1 blockades when they engulfed hSNPs, but it is much less likely that individual immune cells could receive both CTLA-4 and PD-1 blockades as many of them may not take both pSNPs and cSNPS from pSNPs & cSNPs. Further results revealed that the synergistic immune stimulatory effects of CTLA-4 and PD-1 blockades in the form of hSNPs were at least partly through regulating the immune suppressive function of both Tregs and TIM3+ exhausted-like CD8 T cells and allowing effector T cells to expand. This mechanism is not identical to earlier reported mechanisms of CTLA-4 and PD-1 blockades.
研究领域:
癌症免疫治疗
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2024
·
IF 2.3
Huafeng Yang,Hui Liu,Yuan Zheng,Bo Li,Shujing Wang,Jun Zhang,Jiandong Wang
Cornus officinalis total glycosides (COTG) derived from the traditional Chinese medicine Cornus officinalis, is a natural immunosuppressant and has been extensively studied in immunomodulation and immunosuppression. This study aimed to explore the effects of COTG on granulomatous lobular mastitis (GLM) and its associated mechanisms. Compared to the model group, COTG effectively ameliorated histopathological damage to breast tissue, reduced mammary gland suppuration, and enhanced the blood-milk barrier. Additionally, COTG treatment reduced the total number of T cells and B cells in GLM rats, significantly improving clinical indicators such as P-selectin, E-selectin, and intercellular cell adhesion molecule-1. We also observed downregulation of CD28 and B7 expression levels, an upregulation of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expression, and a significant decrease in inflammatory marker levels in the COTG group. COTG exerts an anti-inflammatory effect in GLM by stimulating CTLA-4, inhibiting the B7-CD28 signaling pathway affecting T cell activation, and promoting the blood-milk barrier. These findings suggest that COTG could be a promising therapeutic option for managing GLM, potentially improving patient outcomes by modulating immune responses and reinforcing the blood-milk barrier.
研究领域:
药理学
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免疫学
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病理学
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中医药
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2019
·
IF 3.361
Gao Chao,Xiaoli Li,Yahong Ji,Ying Zhu,Na Li,Nana Zhang,Zunyong Feng,Min Niu
High expression levels of miR-155 are involved in the pathogenesis of inflammatory bowel disease (IBD). We observed an increase in miR-155 in peripheral regulatory T (Treg) cells from IBD patients . Mice that specifically overexpress miR-155 in Foxp3+ Treg cells exhibit spontaneous autoimmunity and more severe dextran sulfate sodium (DSS)-induced intestinal injury . MiR-155 overexpression can lead to a lack of follicular Treg (Tfr) cells and central Treg (cTreg), whereas DSS treatment further depletes the Tfr cells. Furthermore, miR-155 can target the expression of CTLA-4 in cTreg and Tfr, directly inhibiting Tfr cell production and promoting enhanced germinal center (GC) B cell activation and autoantibody overproduction. This outcome may be the cause of severe intestinal injury in patients with autoimmune IBD.
研究领域:
免疫学
·
胃肠病学
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分子生物学
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DOI
PubMed
高影响因子
Science China-Life Sciences
·
2026
·
IF 9.6
Ye Hanyi,Jin Wei,Feng Yifan,Wu Ze,Sun Shuhui,Cui Mengyao,Lv Shun,Jin Bing,Liu Chang,Wang Siming,Li Ying,Dong Zhengqi
Breast cancer remains a therapeutic challenge due to its high malignancy and the lack of safe and effective treatments. Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated remarkable efficacy against various malignancies by enhancing antitumor immunity when used in combination with chemotherapy. However, conventional antibody-based therapies are associated with adverse effects. Plant-derived microRNAs capable of regulating gene expression represent a highly promising alternative strategy, with substantial potential in disease treatment. In this study, we identified that miR152, a plant-derived microRNA from Taxus×media Rehder, has antitumor activity. Our results demonstrated that miR152 exerts antitumor immune activity by silencing CTLA-4 expression in regulatory T cells. Furthermore, we observed that miR152 maintains a favorable safety profile in normal cells at therapeutic doses, while eliciting direct cytotoxic effects on specific cancer cell lines at higher concentrations. In a mouse tumor model, the combination of anti-CTLA-4 miRNA with doxorubicin significantly improved the efficacy of both monotherapies. Mechanistically, miR152 augmented the antitumor immune response by reducing the proportion of Treg cells within the T-cell compartment and increasing the proportion of CD8 + cytotoxic T cells at tumor sites, enhancing the secretion of Th1- and M1-associated cytokines and suppressing interleukin-10 production. This study reveals for the first time that plant-derived miR152 may serve as a cancer immunotherapy agent in combination with a chemotherapeutic drug to inhibit cancer growth in mammals.
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2025
·
IF 30.9
Yizeng Fan,Weichao Dan,Yuzhao Wang,Zhiqiang Ma,Yanlin Jian,Tianjie Liu,Mengxing Li,Zixi Wang,Yi Wei,Bo Liu,Peng Ding,Yuzeshi Lei,Chendong Guo,Jin Zeng,Xiaolong Yan,Wenyi Wei,Lei Li
Itaconate is a metabolite catalyzed by cis- aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEURON
·
2025
·
IF 15
Tao Qin,Tao Jiang,Zihan Zhou,Mengyuan Wu,Yuanzhen Zhang,Zhenqi Yang,Ziyang Zheng,Jiang Yi,Xiaowei Wang,Mingran Luo,Peng Gao,Jiayun Liu,Yifan Huang,Hao Liu,Qingqing Li,Wei Zhou,Shujun Zhang,Xiaodong Guo,Baorong He,Yongxiang Wang,Jin Fan,Shujie Zhao,Jian Chen,Guoyong Yin
The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.
研究领域:
免疫学
·
神经科学
·
分子生物学
·
转化医学
·
炎症与修复
·
神经免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Junhong Li,Wenxing Lv,Ziwei Han,Yike Li,Jinqi Deng,Yanjuan Huang,Shuo Wan,Jiashu Sun,Bo Dai
Chemo-immunotherapy, combining systemic chemotherapeutic drugs and immune checkpoint blockers, is a promising paradigm in cancer treatment. However, challenges such as limited induction of immune responses and systemic immune toxicity have hindered its clinical applications. Here, a zeolite imidazolate framework-8 (ZIF-8) that encapsulates mitoxantrone (MIT), an immune cell death (ICD)-inducing chemotherapeutic agent (MIT@ZIF-8), is synthesized using a one-pot aqueous-phase process. ZIF-8 serves as a dual-functional nanomaterial for chemo-immunotherapy: a carrier to enhance tumor uptake of MIT for improved chemotherapy efficacy, and a pyroptosis inducer to amplify MIT-induced ICD for augmented anti-tumor immune responses. As a result, in vivo administration of MIT@ZIF-8 markedly inhibits tumor growth in both immunologically “hot” colon cancer and immunologically “cold” prostate cancer. Moreover, MIT@ZIF-8 treatment increases the abundance of cytotoxic CD8 + T cells and reduces the amount of immunosuppressive regulatory T cells in tumors, thereby enhancing anti-tumor immunity and sensitizing prostate cancer to anti-CTLA-4 immunotherapy. In summary, MIT@ZIF-8 offers a highly translational approach for chemo-immunotherapy.
研究领域:
肿瘤学
·
纳米医学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
CELL
·
2020
·
IF 38.637
Adrienne M. Luoma,Shengbao Suo,Hannah L. Williams,Tatyana Sharova,Keri Sullivan,Michael Manos,Peter Bowling,F. Stephen Hodi,Osama Rahma,Ryan J. Sullivan,Genevieve M. Boland,Jonathan A. Nowak,Stephanie K. Dougan,Michael Dougan,Guo-Cheng Yuan,Kai W. Wucherpfennig
Summary Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
研究领域:
免疫学
·
肿瘤学
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Jiamei Li,Yang Zhou,Jiaqi Liu,Xiaotong Yang,Kai Zhang,Lei Lei,Haili Hu,Huilin Zhang,Liang Ouyang,Huile Gao
As an endogenous gasotransmitter , CO has achieved tremendous advances in cancer treatment through selectively killing cancer cells. However, the application of CO in tumor immunotherapy has not been reported and the tumor targeting delivery is still a tremendous challenge. Herein, thermosensitive boronic acid group-containing CO prodrug was synthesized and fabricated with tannic acid (TA) and iron (Fe) to form metal-phenolic networks, and then loaded with near-infrared (NIR) photothermal agent IR820 to form [email protected] III TA for combinational therapy of CO and photothermal therapy . Ferroptosis can also be enhanced due to the Fe 3+ incorporation. After TA reduced Fe 3+ into Fe 2+ , Fe 2+ might lead to intracellular Fenton reaction. Furthermore, in combination with CTLA-4 blockade immunotherapy, [email protected] III TA remarkably inhibited breast tumor growth, suppressed the lung metastasis and improved the antitumor immune response. To summarize, [email protected] III TA provides a potential novel option for CO/photothermal/immune synergistic therapy with enhanced ferroptosis through simple compositions and facile synthesis process.
研究领域:
癌症治疗
·
药学
·
材料科学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NANOTECHNOLOGY
·
2021
·Vol. 32
·期 42
·425101
·
IF 3.874
Qing Zhang,Lian Wu,Shaozheng Liu,Qingjie Chen,Lingpeng Zeng,Xuezhong Chen,Qing Zhang
Photodynamic therapy (PDT) and immunotherapy have been often adopted for ovarian cancer therapy, yet their application is limited by the high recurrence rate and toxic side effects. Intriguingly, nanoparticles contribute to enhancing the performance of PDT. Here, we investigated the synthesis of HER-2-Nanobody (Nb)-conjugated human serum albumin (HSA) incorporated with chlorin (Ce6) and catalase (CAT) (Nb@HCC), and analyzed the synergic effect of Nb@HCC-mediated PDT and immunotherapy for SK-OV-3 tumors. The Ce6 and CAT were incorporated into HSA to construct the HCC nanoparticles. HER-2-Nanobody was the purified bacterial crude extract, and conjugated with HCC to prepare Nb@HCC via heterodisulfide. The effects of Nb@HCC with near infrared ray (NIR) irradiation on moderating hypoxia and hypoxia inducible factor-1α (HIF-1α) expression were evaluated in the SK-OV-3 cells and tumor tissues. A SK-OV-3 tumor-bearing model was developed, where the synergistic effect of Nb@HCC-mediated PDT and anti-CTLA-4 therapy was investigated. Nb@HCC with a 660 nm laser irradiation could induce massive reactive oxygen species and trigger apoptosis in SK-OV-3 cells. Nb@HCC and PDT promoted danger-associated molecular patterns (DAMPs), which indicated immunogenic cell death and maturation of dendritic cells in the SK-OV-3 cells. Irradiated by NIR, Nb@HCC alleviated the hypoxia and decreased the expression of HIF-1α. The Nb@HCC-mediated PDT and anti-CTLA-4 therapy synergically inhibited the progression of distant tumor, and induced T cell infiltration. Biosafety tests suggested that Nb@HCC would not cause damage to the major organs with less toxicity and side effects. To conclude, a combination of Nb@HCC-mediated PDT and anti-CTLA-4 therapy could inhibit the progression of distant tumor to attain remarkable therapeutic outcomes.
研究领域:
肿瘤学
·
纳米技术
·
免疫治疗
·
药学
✓ 已验证
DOI
PubMed
高影响因子
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