ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Di Chuan,Rangrang Fan,Bo Chen,Yangmei Ren,Min Mu,Haifeng Chen,Bingwen Zou,Haohao Dong,Aiping Tong,Gang Guo
In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid–polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.
研究领域:
癌症研究
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纳米技术
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免疫学
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分子生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Huajin Zhang,Fujun Liu,Junyilang Zhao,Yong Wang,Yuge Shen,Qiqi Li,Hui Luo,Yu Chen,Rong Li,Fan Zhu,Shuo Xie,Yinhao Wei,Xupeng Gou,Danling Hu,Zhengji Li,Hanshuo Yang
Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable promise in treating hematological malignancies. However, the ex vivo expansion of CAR-T cells is time-consuming, potentially impairing CAR-T cells function. Physiologically, T cell activation and proliferation occur within the lymph node (LN) paracortex, a dynamic environment structured by a three-dimensional (3D) reticular network (RN) that promotes cell migration and mediator delivery. Mimicking this physiological niche offers a compelling strategy to improve CAR-T cell expansion. Inspired by the structure of RN, we developed a biomimetic RN-like poriferous microsphere (PM) to establish a 3D culture platform optimized for both T cell and CAR-T cell proliferation. This engineered system not only significantly enhanced the proliferation rates of human T cells and CAR-T cells compared to conventional methods, but also preserved a higher proportion of central memory T cells (TCM) and reduced the expression of exhaustion markers (PD-1, TIM-3, and LAG-3). Moreover, CAR-T cells expanded in PMs exhibited superior anti-tumor efficacy in both ex vivo and in vivo models, which correlated with the enrichment of pathways associated with robust T cell function at the RNA level. Over all, this biomimetic platform addresses critical limitations in human T/CAR-T cell expansion, preserving cell function and improving therapeutic outcomes.
研究领域:
免疫治疗
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生物工程
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癌症生物学
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细胞治疗
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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
Acta Pharmaceutica Sinica B
·
2023
·
IF 14.5
Siqin He,Lulu Wang,Dongxu Wu,Fan Tong,Huan Zhao,Hanmei Li,Tao Gong,Huile Gao,Yang Zhou
A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8 + T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β -cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β -carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.
研究领域:
肿瘤学
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药剂学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Arthritis & Rheumatology
·
2025
·
IF 10.9
Jin-Fen Ma,Ting Xu,Hao-Xian Zhu,Xiao-Min Chen,Liang Li,Zhi-Bin Zhao,Liwei Lu,Yang Li,Zhe-Xiong Lian,Cai-Yue Gao
Objective Activated T cells play a pivotal pathogenic role in the progression of Sjögren disease (SjD); however, there are currently no targeted therapies specifically designed to address them. This study aims to identify pathogenic CD8 + T cells in SjD and develop targeted therapeutic strategies. Methods Il12b-/-Il2ra-/- mice, a murine model for overlapping primary biliary cholangitis and SjD, were employed in this study. Pathogenic CD8 + T cells were identified through single-cell RNA sequencing and flow cytometry analyses of samples from both patients with SjD and relevant murine models. Shared T cell receptor analysis was conducted to trace the potential precursors of pathogenic CD8 + T cells. The efficacy of PD-1-targeted chimeric antigen receptor (CAR)–T cell therapy was evaluated through the assessment of salivary gland secretory function, immunologic profiles, and histopathological changes in the murine model. Results We identified PD-1 as a comprehensive marker of clonally expanded and activated pathogenic CD8 + T cells in the salivary glands and peripheral tissues. Flow cytometry further confirmed the activation phenotype and cytotoxicity of PD-1 + CD8 + T cells in the salivary glands of patients with SjD. Notably, the number of PD-1 + CD8 + T cells in the labial glands positively correlated with disease activity in patients with SjD. These findings highlight the therapeutic potential of depleting PD-1 + CD8 + T cells in SjD. Furthermore, PD-1-targeted CAR-T cell therapy significantly alleviated SjD symptoms in a murine model. Conclusion We identified the pathogenic role of PD-1 + CD8 + T cells in both patients with SjD and a murine model and demonstrated the efficacy of PD-1-targeted CAR-T cell therapy in SjD model mice. Our findings suggest a promising avenue for developing clinical therapeutic strategies for patients with SjD.
研究领域:
免疫学
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医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cancer Cell International
·
2024
·Vol. 24
·期 1
·1-15
·
IF 5.3
Cen Lanqi,Zhang Zhe,Sun Yi,Wu Nandie,Shao Jie,Qian Zhaoye,Tian Manman,Ke Yaohua,Liu Baorui
Background The clinical application of peptide vaccines in tumor immunotherapy holds significant promise. Peptide-based tumor vaccines are currently subject to certain limitations in clinical trials, including the challenge of inducing a sustained response from CD4 + T helper cells and cytotoxic T lymphocytes (CTL), as well as human leukocyte antigen (HLA) restrictions. Methods Through the utilization of biological information methodology, a screening process was conducted to identify three potential long peptides that are specifically targeted by the MAGE-A4 antigen. The candidate long peptides were subjected to in vitro testing using human peripheral blood lymphocytes as samples to evaluate their immunogenicity and immune function. The antitumor properties and preliminary mechanism of the long peptide vaccine were investigated through the use of a mouse model designed for the prevention of triple negative breast cancer (TNBC). Results Three predicted multi-epitope long peptides targeting MAGE-A4 have shown to have a strong immunogenicity, with a total positive rate of 72% across different HLA subtypes in Chinese populations. they can also increase the levels of the costimulatory factor CD137 and tumor necrosis factor-alpha (TNF-α), activate T cells, and boost the cytotoxic activity. Results from an animal study have revealed that the long-peptide vaccine, both on its own and in combination with R848, has displayed impressive anti-tumor and target-specific capabilities. Moreover, it has the ability to increase the expression of effector memory T cells and central memory T cells. Conclusions This study was the first to screen three multi-epitope long peptides targeting MAGE-A4 and assess their immunogenicity, immune function, and potential as adjuvant peptides. The results showed that the MAGE-A4 long peptide vaccine can be used as a novel immunoprophylaxis method to prevent TNBC. Moreover, the proposed development model is capable of screening multiple target antigens, which lead to its clinical application.
研究领域:
肿瘤学
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免疫学
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疫苗学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yinghao Ding,Xueying Zhu,Jian Wen,Junchao Xiong,Shengyi Zhang,Zhimou Yang,Zhi-Wen Hu
Antigen presentation deficiency restricted by class I major histocompatibility complex (MHC-I) causes low antigenicity and antigen escape in tumors, thereby limiting T-cell immunotherapy outcomes. Here, a combined tumor immunotherapy is developed, in which tumors can present exogenous non-tumor antigens, and adoptively transferred CD8 + T cells specific for these antigens are re-targeted to attack tumors. The approach leverages a cascade-responsive peptide self-assembly to co-deliver suitable antigens and the chemotherapeutic drug camptothecin (CPT) to tumors. As a proof-of-concept, to re-target ovalbumin (OVA)-specific OT-I CD8 + T cells against tumors, PSA (Nap-GFFpYE-ss-Ag) and CPSA (CPT-GFFpYE-ss-Ag) are constructed, containing an OVA-derived epitope OVA 257-264 and/or CPT. The design enables the release of a unique N-terminal extended OVA 257-264 and CPT into the cytosol. As a result, the extended antigen is efficiently presented on the tumor surface by MHC-I, and CPT further enhances this presentation. When combined with adoptively transferred OT-I CD8 + T cells, the approach effectively facilitates CD8 + T cell infiltration and tumor inhibition. Additionally, CPSA treatment sensitizes immune responses to programmed cell death-ligand 1 (PD-L1) blockade, allowing the approach to synergize with an anti-PD-L1 antibody for improved tumor eradication.
研究领域:
肿瘤免疫学
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纳米医学
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药物递送系统
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免疫治疗
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分子自组装
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Yuetao Zhao,Zuozhong Xie,Yiyi Deng,Aji Huang,Yilang He,Bin Wen,Xiaoxiao Liao,Ruimin Chang,Guanxiong Zhang,Lin Zhu,Yanpeng Wang,Tan Li,Yanqing Zhong,Jun Zuo,Hailun Zhang,Miao Chen,Jing Liu,Xiang Chen,Hong Liu
Immunotherapy has partly achieved striking outcomes in the clinic for specific tumors. However, the responses are still limited for tumors that have restricted filtration and decreased activity of cytotoxic T cells due to the tumor stroma physical obstacles and immune-suppressive factors. Here we report an effective synergistic strategy for tumor therapy via integrating photothermal therapy and blockade of metabolic immune pathway adenosine based on a novel black phosphorus nanobomb. By rational conjugation of adenosine A2A receptor inhibitor SCH442416 (SCH) and targeting aptamer AS1411 (Apt) on black phosphorus nanosheets (BPs), we fabricate an immunostimulant nanobomb [email protected] @BPs. [email protected] @BPs shows good targeting and accumulation in melanoma. By synergism of photothermia and adenosine blockade, [email protected] @BPs could not only directly ablate tumor cells, but also boost maturation of dendritic cells, inhibit the regulatory T cells, stimulate the cytotoxic T cells, and elicit their filtration by attenuating tumor stromal barriers (e. g., cancer-associated fibroblasts and collagen). This synergistical therapy efficiently suppresses the growth of melanoma, and might be potential for other solid tumors.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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生物医学工程
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产品关联
DOI
高影响因子
Mucosal Immunology
·
2024
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IF 7.9
Xixi Huang,Tingxuan Yin,Min Yu,Guohua Zhu,Xianyang Hu,Hailin Yu,Weijie Zhao,Jiajia Chen,Jiangyuan Du,Qingyu Wu,Wei Zhang,Lu Liu,Meirong Du
Decidual CD8 + T (dCD8 + T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent uterine environments before and during pregnancy, respectively, and the composition and phenotypic alterations of uterine CD8 + T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8 + T and endometrial CD8 + T (eCD8 + T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8 + T (pCD8 + T) cells. However, dCD8 + T cells showed decreased expression of coinhibitory (PD-1), chemotaxis (CXCR3), and tissue-resident (CD69 and CD103) markers and increased granzyme B and granulysin expression compared to eCD8 + T cells. In vitro, cytotoxicity assays demonstrated greater effector functions in dCD8 + T cells than in eCD8 + T cells. Further in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8 + T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrated dCD8 + T cells replenished from the circulation retained their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.
研究领域:
免疫学
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生殖生物学
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妊娠免疫学
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DOI
PubMed
高影响因子
Nano Research
·
2020
·Vol. 13
·期 12
·3403-3415
·
IF 8.183
Zeng Fanchu,Qin Huan,Liu Liming,Chang Haocai,Chen Qun,Wu Linghua,Zhang Le,Wu Zhujun,Xing Da
Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL SCIENCE
·
2023
·Vol. 30
·期 1
·1-19
·
IF 11
Li Peisi,Zhou Dawang,Chen Dongwen,Cheng Yikan,Chen Yuan,Lin Zhensen,Zhang Xi,Huang Zhihong,Cai Jiawei,Huang Wenfeng,Lin Yanyun,Ke Haoxian,Long Jiahui,Zou Yifeng,Ye Shubiao,Lan Ping
Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8 + T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8 + T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8 + T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8 + T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8 + T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8 + T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8 + T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Xiejun Zhao,Xiangchuan Qin,Ruizhe Wang,Yawen Wang,Yinli He,Yuchen Wang,Kefeng Li,Peipei Zhang,Chen Yang,Menghan Wang,Yingtong Dong,Xue Shi,Jia Ma,Jiye Zhang,Xiaojiao Li
Inefficient priming, poor recruitment, and inadequate reinvigoration of T cells challenges the therapy of PD-L1-resistant tumors. Herein, a pH-responsive charge-reversal nanoplatform integrating coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor (iCARM1) and poliovirus receptor siRNA (siPVR) is developed. Upon tumor penetration, iCARM1 released in tumor cells facilitates T cell priming by epigenetically activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling-mediated dendritic cell maturation. Meanwhile, in T cells, iCARM1 facilitates their recruitment by upregulating CXC-chemokine receptor 3 (CXCR3) expression. The released siPVR silences pvr to reinvigorate T cells. This epigenetic nanoagonist induces a robust immune response, dramatically suppresses tumor growth, metastasis, and relapse, and confers durable protection against secondary tumor challenge. Multiple PD-L1-resistant models demonstrate the broad applicability of this strategy. This study thus represents an innovative approach for facilitating multilevel T cell responses to combat PD-L1-resistant tumors.
研究领域:
癌症免疫治疗
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纳米医学
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表观遗传学
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分子生物学
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免疫学
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信号转导
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RNA干扰
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·1-20
·
IF 52.7
Ma Xiao,Chen Jiao,Wang Fang,Fan Xinzou,Li Zhenhong,Liang Hantian,Cheng Hao,Nan Fang,Lin Yubin,Song Xiaoshuang,Zhang Jianan,Gao Fan,Zhang Wei,Jin Wenwen,Zhang Huiyuan,Tong Jiyu,Jiang Hong,Zhou Xikun,Zou Qiang,Hu Hongbo,Tong Aiping,Chen WanJun,Zhang Dunfang
The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.
研究领域:
免疫学
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营养学
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细胞生物学
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代谢
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胃肠病学
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药理学
✓ 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）