International Journal of Nanomedicine
·
2022
·
IF 7.033
An-Ran Shen,Xiao-Xiao Jin,Tao-Tao Tang,Yan Ding,Xiao-Tao Liu,Xin Zhong,Yan-Dan Wu,Xue-Lian Han,Guang-Yu Zhao,Chuan-Lai Shen,Lin-Li Lv,Bi-Cheng Liu
Purpose Current vaccines for the SARS-CoV-2 virus mainly induce neutralizing antibodies but overlook the T cell responses. This study aims to generate an exosomal vaccine carrying T cell epitope peptides of SARS-CoV-2 for the induction of CD8 + T cell response. Methods Thirty-one peptides presented by HLA-A0201 molecule were conjugated to the DMPE-PEG-NHS molecules, and mixed with DSPE-PEG to form the peptide-PEG-lipid micelles, then fused with exosomes to generate the exosomal vaccine, followed by purification using size-exclusion chromatography and validation by Western blotting, liquid nuclear magnetic resonance (NMR) test and transmission electron microscopy. Furthermore, the exosomal vaccine was mixed with Poly (I:C) adjuvant and subcutaneously administered for three times into the hybrid mice of HLA-A0201/DR1 transgenic mice with wild-type mice. Then, the epitope-specific T cell responses were detected by ex vivo ELISPOT assay and intracellular cytokine staining. Results The exosomal vaccine was purified from the Peak 2 fraction of FPLC and injected into the hybrid mice for three times. The IFN-γ spot forming units and the frequencies of IFN-γ + /CD8 + T cells were 10–82-fold and 13–65-fold, respectively, higher in the exosomal vaccine group compared to the Poly (I:C) control group, without visible organ toxicity. In comparison with the peptides cocktail vaccine generated in our recent work, the exosomal vaccine induced significantly stronger T cell response. Conclusion Exosomal vaccine loading T cell epitope peptides of SARS-CoV-2 virus was initially generated without pre-modification for both peptides and exosomes, and elicited robust CD8 + T cell response in HLA-A transgenic mice.
研究领域:
免疫学
·
病毒学
·
分子生物学
·
疫苗研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2023
·
IF 29
Qingqing Zhang,Qing Zhao,Tao Li,Longya Lu,Fei Wang,Hong Zhang,Zhi Liu,Huihui Ma,Qihui Zhu,Jingjing Wang,Xuemei Zhang,Yang Pei,Qisha Liu,Yuyu Xu,Jinlong Qie,Xiaoting Luan,Zhibin Hu,Xingyin Liu
Previous studies have shown that Lactobacillus species play a role in ameliorating colorectal cancer (CRC) in a mouse model. However, the underlying mechanisms remain largely unknown. Here, we found that administration of a probiotic strain, Lactobacillus plantarum L168 and its metabolite, indole-3-lactic acid, ameliorated intestinal inflammation, tumor growth, and gut dysbiosis. Mechanistically, we indicated that indole-3-lactic acid accelerated IL12a production in dendritic cells by enhancing H3K27ac binding at the enhancer regions of IL12a that contributed to priming CD8+ T cell immunity against tumor growth. Furthermore, indole-3-lactic acid was found to transcriptionally inhibit Saa3 expression related to cholesterol metabolism of CD8+ T cells through changing chromatin accessibility and subsequent enhancing function of tumor-infiltrating CD8+ T cells. Together, our findings provide new insights into the epigenetic regulation of probiotics-mediated anti-tumor immunity and suggest the potential of L. plantarum L168 and indole-3-lactic acid to develop therapeutic strategies for patients with CRC.
研究领域:
癌症生物学
·
免疫学
·
微生物学
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMISTRY OF MATERIALS
·
2021
·
IF 9.811
Jiexin Li,He Ren,Yaping Sun,Gengqi Liu,Xingyue Yang,Qian Qiu,Yuanmeng Ding,Jonathan F. Lovell,Yumiao Zhang
Cancer peptide vaccines face challenges for antigen delivery and presentation. In the present work, we develop a self-assembled magnetic micelle delivery system for CD8+ T-cell epitopes that produces strong cellular immune responses. Hydrophobically modified imiquimod R837 and Zn1.15Fe1.85O4 are coencapsulated in the core of Pluronic F127 block copolymer micelles. Magnetic Zn1.15Fe1.85O4 enables externally targeted delivery and enrichment of micelles in lymph nodes. Furthermore, metal ions are found to enhance vaccine immunogenicity. F127 micelles were chemically modified by a self-immolative linker so that antigens are rapidly and reversibly grafted on micelles in an aqueous solution. With the assistance of an external magnetic field, once the magnetic micelles are delivered to lymph nodes and taken up by immune cells, intracellular glutathione cleaves the disulfide bond and releases pristine short peptide antigen. Delivery to lymph nodes is tracked by magnetic resonance and fluorescence imaging. The use of this vaccine system eradicated tumors in a murine tumor model. Thus, integrating multiple functionalities in a single micellar delivery system, including responsive linkage, multiple immunostimulatory molecules, targeted delivery, and bimodal imaging, demonstrates the potential for theranostic approaches to develop a new generation of cancer vaccines.
研究领域:
癌症研究
·
免疫学
·
纳米技术
·
生物医学工程
·
治疗诊断学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR IMMUNOLOGY
·
2024
·
IF 3.2
Zhou Si Yun,Song Zhihua,Tian Xuelian,Xia Min,Hu Rongjing,Luo Mei
Chlamydia trachomatis (CT) is the leading cause of bacterial sexually transmitted diseases worldwide, which can cause diseases such as pelvic inflammatory disease, and cervical and fallopian tube inflammation, and poses a threat to human health. Rosmarinic acid (RosA) is an active ingredient of natural products with anti-inflammatory and immunomodulatory effects. This study aimed to investigate the role of RosA in inhibiting autophagy-regulated immune cells-CD8+ T cells via the Ras/Raf/MEK/ERK signaling pathway in a CT-infected mouse model. Mice were inoculated with CT infection solution vaginally, and the mechanistic basis of RosA treatment was established using H&E staining, flow cytometry, immunofluorescence, transmission electron microscopy, and western blot. The key factors involved in RosA treatment were further validated using the MEK inhibitor cobimetinib. Experimental results showed that both RosA and the reference drug azithromycin could attenuate the pathological damage to the endometrium caused by CT infection; flow cytometry showed that peripheral blood CD8+ T cells increased after CT infection and decreased after treatment with RosA and the positive drug azithromycin (positive control); immunofluorescence showed that endometrial CD8 and LC3 increased after CT infection and decreased after RosA and positive drug treatment; the results of transmission electron microscopy showed that RosA and the positive drug azithromycin inhibited the accumulation of autophagosomes; western bolt experiments confirmed the activation of autophagy proteins LC3Ⅱ/Ⅰ, ATG5, Beclin-1, and p62 after CT infection, as well as the inhibition of Ras/Raf/MEK/ERK signaling. RosA and azithromycin inhibition of autophagy proteins activates Ras/Raf/MEK/ERK signaling. In addition, the MEK inhibitor cobimetinib attenuated RosA's protective effect on endometrium by further activating CD8+ T cells on a CT-induced basis, while transmission electron microscopy, immunofluorescence, and western blots showed that cobimetinib blocked ERK signals activation and further induced phagocytosis on a CT-induced basis. These data indicated that RosA can activate the Ras/Raf/MEK/ERK signaling pathway to inhibit autophagy, and RosA could also regulate the activation of immune cells-CD8+T cells to protect the reproductive tract of CT-infected mice.
研究领域:
免疫学
·
微生物学
·
药理学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2025
·
IF 19.8
Bai Ying,Ren Hui,Leng Shuo,Yuan Mengqin,Jiang YiXin,Zhang Shenyang,Wang Yu,Ju Minzi,Wang Zhi,Xi Wen,Xu Lian,Zheng Bingjing,Li Daxing,Huo Xinchen,Zhu Tianhao,Zhang Beicheng,Shen Ling,Zhang Yuan,Jiang Wei,Zhang John H.,Han Bing,Yao Honghong
Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK + CD8 + CD27 + CCR7 + T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.
研究领域:
神经科学
·
免疫学
·
卒中研究
·
神经免疫学
·
分子生物学
·
细胞生物学
·
生物医学研究
·
药理学
·
系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-20
·
IF 11.4
Xu Wenjing,Li Yingqiu,Liu Lumei,Xie Jing,Hu Zongren,Kuang Shida,Fu Xinying,Li Bonan,Sun Tiansong,Zhu Congxu,He Qinghu,Sheng Wen
Background Prostate cancer (PCa) incidence and mortality rates are rising. Our previous research has shown that the combination of icariin (ICA) and curcumol (CUR) induced autophagy and ferroptosis in PCa cells, and altered lipid metabolism. We aimed to further explore the effects of the combination of ICA and CUR on gut microbiota, metabolism, and immunity in PCa. Methods A mouse subcutaneous RM-1 cell tumor model was established. 16 S rRNA sequencing was performed to detect changes in fecal gut microbiota. SCFAs in mouse feces, and the effect of ICA-CUR on T-cell immunity, IGFBP2, and DNMT1 were examined. Fecal microbiota transplantation (FMT) was conducted to explore the mechanism of ICA-CUR. Si-IGFBP2 and si/oe-DNMT1 were transfected into RM-1 and DU145 cells, and the cells were treated with ICA-CUR to investigate the mechanism of ICA-CUR on PCa development. Results After treatment with ICA-CUR, there was a decrease in tumor volume and weight, accompanied by changes in gut microbiota. ICA-CUR affected SCFAs and DNMT1/IGFBP2/EGFR/STAT3/PD-L1 pathway. ICA-CUR increased the positive rates of CD3 + CD8 + IFN-γ, CD3 + CD8 + Ki67 cells, and the levels of IFN-γ and IFN-α in the serum. After FMT (with donors from the ICA-CUR group), tumor volume and weight were decreased. SCFAs promote tumor development and the expression of IGFBP2. In vitro, DNMT1/IGFBP2 promotes cell migration and proliferation. ICA-CUR inhibits the expression of DNMT1/IGFBP2. Conclusions ICA-CUR mediates the interaction between gut microbiota and the DNMT1/IGFBP2 axis to inhibit the progression of PCa by regulating immune response and metabolism, suggesting a potential therapeutic strategy for PCa.
研究领域:
肿瘤学
·
免疫学
·
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Communications
·
2026
·
IF 28.4
Nianke Zang,Jinfeng Gan,Ye Chen,Zheng Huang,Chichu Xie,Junlong Dang,Changyuan Huang,Linjie Yang,Xuelian Chen,Guangli Rong,Jianbo Sun,Yiming Shao,Julie Wang,Guangying Qi,Yu Liu,Song Guo Zheng
Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topkfl/fl and Cd8CreTopkfl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8CreTopkfl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2026
·
IF 18.1
Lin Zhenyu,Chen Huanpeng,Ke Yujing,Xiao Hanyue,Li Chao,Wu Zilong,Gao Huixin,Huang Nanqi,Lu Lijuan,Sun Peng,Bian Yingjie
While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8 + T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8 + T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8 + T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8 + T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8 + T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.
✓ 已验证
DOI
PubMed
高影响因子
Exploration
·
2025
·
IF 22.5
Panpan Xue,Tingjie Bai,Huilan Zhuang,Angelo H. All,Shuangqian Yan,Xuemei Zeng
Stimulating the immunogenic cell death (ICD) by chemical and photothermal agents triggers antitumor immune responses to tumor treatments. However, the abnormal cholesterol accumulation in cancer cells promotes tumor survival and metastasis, while the high concentration of cholesterol in the tumor microenvironment will result in T exhaustion. Herein, a cholesterol-regulable nanoliposome (ictLipo) that encapsulated with IR806, tirapazamine, and cholesterol oxidase (ChOx) was fabricated to boost chemo/photothermal-activated ICD and antitumor immune responses. Specifically, the released ChOx oxidizes cholesterol, accompanied by oxygen consumption and ATP reduction. Whereupon, tumoral anabatic hypoxia activates the toxicity of tirapazamine while ATP reduction strengthens photothermal therapy of the IR806 by suppression of HSP70. We found that this interactive strategy evokes robust ICD and reverses T-cell exhaustion. When combined with the immune checkpoint blockade, ictLipo can efficiently restrain breast cancer metastasis in two tumor models. The interactive strategy sheds new light on the immunological facet of cholesterol metabolism and may provide a new therapeutic strategy against breast cancer.
研究领域:
癌症免疫治疗
·
纳米医学
·
肿瘤微环境
·
免疫代谢
·
光热治疗
✓ 已验证
产品关联
DOI
高影响因子
CANCER CELL
·
2026
·
IF 56.1
Zikun Ma,Yuzhao Wang,Weikai Wang,Wanyang Sun,Rong Wang,Xue Ding,Zibin Chen,Xiangdong Li,Zhiyong Li,Yunlin Ye,Yize Mao,Jianhua Yin,Guibo Li,Rong-Rong He,Xiaoyu Liang,Zhuowei Liu
Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment, yet how their metabolic states shift during therapy and influence anti-tumor immunity remains unclear. By integrating clinical cancer samples, single-cell RNA analyses, and functional studies, we identify a chemotherapy-conditioned PTGER3 + CAF subset characterized by enhanced lipid oxidation. This metabolic reprogramming strengthens antitumor immunity by promoting CD8 + T cell activation and cytotoxicity through the suppression of PTEN-related signaling. Clinically, higher proportions of therapy-induced PTGER3 + CAFs correlate with improved treatment responses and better patient prognosis. Together, these findings reveal a previously unrecognized stromal metabolic adaptation that supports CD8 + T cell immunity and highlight CAF-driven lipid oxidation and its regulation of CD8 + T cell PTEN signaling as potential avenues to enhance chemotherapy and immunotherapy efficacy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Yang Di,Liu Jia,Gao Yan,Guan Xin,Tong Rui
Cervical cancer (CC) is a prevalent malignancy in women; however, the efficacy of immunotherapy in this disease is suboptimal, highlighting the need for novel therapeutic targets. We found that low RNF125 expression correlated with poor prognosis in CC patients. In vitro and in vivo, RNF125 inhibited proliferation and induced apoptosis of CC cells. In immunocompetent mice, RNF125 suppressed tumor growth, increased CD8⁺ T cell infiltration, elevated IFN-γ secretion, and reduced PD-1 expression on CD8⁺ T cells. Co-culture experiments confirmed that tumor cells overexpressing RNF125 enhanced CD8⁺ T cell proliferation and function. Further mechanistic investigation revealed that RNF125 promoted CD8⁺ T cell activity by ubiquitinating and degrading PD-L1. Additionally, RNF125 was identified as a direct target of miR-574-5p. This study demonstrates that RNF125 exhibits tumor-suppressive functions in CC by enhancing anti-tumor immunity, highlighting its therapeutic potential.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Medicine
·
2025
·Vol. 23
·期 1
·1-18
·
IF 8.3
Wang Shuang,Xu Le,Jiao Xue,Dong Xiaoyu,Zhong Zhaoyang,Ren Qianhui,Liu Xiaoxuan,Yuan Ming,Wang Guoyun
Background Endometriosis (EM) exhibits localised iron overload. However, the contribution of ferroptosis to EM pathogenesis remains unclear. We investigated how iron overload affects CD8⁺ T cell immune function and the underlying ferroptotic mechanisms. Methods We collected eutopic and ectopic endometrial tissues from 57 patients with stage III–IV EM and eutopic tissues from 31 controls. Iron deposition was assessed by Prussian blue staining; CD8⁺ T cell infiltration by immunohistochemistry; and ferroptosis in CD8⁺ T cells by immunofluorescence and flow cytometry. In vitro and in vivo assays measured CD8⁺ T cell ferroptosis and endometrial stromal cell apoptosis via flow cytometry. Transwell assays evaluated cell migration. Gene and protein expression were analysed via RT-qPCR and Western Blot. We verified the effect of iron overload on the growth of lesions in vivo by constructing a mouse EM model. The role of CD8⁺ T cells in EM progression was tested using a reinfusion model. Results In ectopic EM lesions, CD8⁺ T cells were enriched yet functionally impaired, showing increased ferrous iron accumulation and lipid peroxidation alongside decreased GPX4 expression. In vitro, iron overload reduced CD8⁺ T cell viability, elevated lipid peroxidation, and induced mitochondrial damage—effects reversed by ferroptosis inhibitors. Iron overload upregulated p53 and downregulated xCT and GPX4; p53 inhibition blocked ferroptosis, indicating a p53-dependent pathway. In vivo EM models confirmed that excess iron compromises CD8⁺ T cell function and impairs their recruitment to lesion sites. Conclusions Iron overload induces p53-mediated inhibition of xCT/GPX4, triggering ferroptosis in CD8⁺ T cells and leading to their dysfunction. These insights into ferroptosis–CD8⁺ T cell interactions in EM may guide the development of novel immunotherapeutic strategies. Graphical abstract
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）