MOLECULAR CELL
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2024
·
IF 14.5
Zhenxi Zhang,Yanting Yang,Yang Chen,Jingyu Su,Wenjing Du
The functional integrity of CD8 + T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8 + T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8 + T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8 + T cell activation and anti-tumor immune response in vitro and in vivo . Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8 + T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8 + T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
研究领域:
免疫学
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肿瘤学
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代谢生物学
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产品关联
DOI
PubMed
高影响因子
Mucosal Immunology
·
2024
·
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
HELICOBACTER
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2023
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IF 4.4
Zelin Zhang,Xingchi Chen,Bin Li,Tingting Xia,Xiaobin Wu,Chao Wu
Background Urease subunit B (UreB), a conserved and key virulence factor of Helicobacter pylori ( H. pylori ), can induce the host CD4 + T cell immune responses to provide protection, but less is known regarding CD8 + T cell responses. The characteristics of H. pylori -specific CD8 + T cell responses and the mechanism underlying antigen processing and presentation pathways remain unclear. This study was focus on protective antigen recombinant UreB (rUreb) to detect specific CD8 + T cell responses in vitro and elucidate the mechanism of UreB antigen processing and presentation. Methods The peripheral blood mononuclear cells (PBMCs) collected from H. pylori -infected individuals were stimulated with rUreB in vitro to detect specific CD8 + T cell responses after co-culture with rUreB-pulsed autologous hMDCs. Through blocking assay, we investigated the potential pathway of UreB antigen processing and presentation via the cytosolic pathway or vacuolar pathway. The cytokines production of UreB specific CD8 + T cell were evaluated as well. Results We demonstrated UreB can induce specific CD8 + T cell immune responses in H. pylori infected individuals. Importantly, we characterized that UreB were mainly processed by proteasome instead of lysosomal proteases and presented through cytosolic pathway of cross-presentation, which requires endoplasmic reticulum–Golgi transport and newly synthesized MHC-I molecules, to induce functional-specific CD8 + T cell (IFN-γ + TNF-α + Grz A+ Grz B+) responses. Conclusions These results suggest that H. pylori UreB induces specific CD8 + T cell responses through cytosolic pathway of cross-presentation in infected individuals.
研究领域:
免疫学
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病原生物学
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医学
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DOI
PubMed
高影响因子
Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-13
·
IF 7
Jiang Xiaoxiao,Fan Zhijin,Zhang Zhenzhen,Zeng Fanchu,Sun Tong,Li Yuchen,Huang Guojia,Nie Liming
Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
研究领域:
肿瘤学
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免疫学
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Shijia Lu,Chenxiao Zhang,Huiru Wu,Junjie Wang,Jinglong Wang,Limei Zhao,Tianyang Ren,Guofei Li
Liver cancer is one of the malignant tumors with high morbidity and mortality worldwide and lacks effective clinical treatments. CD8 + T cell-based immunotherapy is the most promising option for the treatment of liver cancer, but its application is severely limited by low infiltration and functional exhaustion of CD8 + T cells in liver cancer tissues. To overcome this problem, in this study, pH/matrix metalloproteinase-9 (MMP-9) dual-responsive liposomes were constructed and co-loaded with a galectin-3 (Gal-3) inhibitor, GB1107, a programmed death receptor 1 (PD-1) inhibitor, BMS1166, and an androgen receptor (AR) antagonist, enzalutamide, for immunotherapy studies in liver cancer. Specifically, the co-loaded liposomes (GBE@LP) were produced with a one-two punch targeting antitumor immunity. First, GBE@LP exhibited prolonged circulation in the blood and accumulated in liver cancer tissues through the enhanced permeability and retention effect due to the presence of surface polyethylene glycol. After entering liver cancer tissues, GBE@LP responded to the low pH and overexpression of MMP-9 in the microenvironment to promote the release of GB1107, BMS1166, and enzalutamide, thus, realizing the intelligent release of drugs targeting liver cancer. Upon reaching liver tumor tissues, GB1107 can inhibit overexpressed Gal-3 to transform liver cancer from a “cold” to a “hot” tumor and enable deep penetration by CD8 + T cells. In addition, BMS1166 and enzalutamide inhibit PD-1 and AR in CD8 + T cells, reversing CD8 + T cell exhaustion and enhancing their killing activity. In vivo and in vitro experiments confirmed the significant antitumor effects of GBE@LP in liver cancer. These results indicate that our strategy is expected to reverse the “cold” tumor and immune exhaustion state of liver cancer, which not only improves therapeutic efficacy, but also provides a new paradigm for the exploration of liver cancer immunotherapy.
研究领域:
肿瘤学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2024
·
IF 18
Daping Xie,Congwei Han,Chonghao Chen,Zhencheng Liao,Senio Campos de Souza,Yiming Niu,João F. Mano,Lei Dong,Chunming Wang
Cancer vaccination holds great promise for cancer treatment, but its effectiveness is hindered by suboptimal activation of CD8 + cytotoxic T lymphocytes, which are potent effectors to mediate anti-tumor immune responses. A possible solution is to switch antigen-presenting cells to present tumor antigens via the major histocompatibility complex class I (MHC-I) to CD8 + T cells – a process known as cross-presentation. To achieve this goal, we develop a three-dimensional (3D) scaffold vaccine to promote antigen cross-presentation by persisted toll-like receptor-2 (TLR2) activation after one injection. This vaccine comprises polysaccharide frameworks that “hook” TLR2 agonist (acGM) via tunable hydrophobic interactions and forms a 3D macroporous scaffold via click chemistry upon subcutaneous injection. Its retention-and-release of acGM enables sustained TLR2 activation in abundantly recruited dendritic cells in situ , inducing intracellular production of reactive oxygen species (ROS) in optimal kinetics that crucially promotes efficient antigen cross-presentation. The scaffold loaded with model antigen ovalbumin (OVA) or tumor specific antigen can generate potent immune responses against lung metastasis in B16-OVA-innoculated wild-type mice or spontaneous colorectal cancer in transgenic Apc Min/+ mice, respectively. Notably, it requires neither additional adjuvants nor external stimulation to function and can be adjusted to accommodate different antigens. The developed scaffold vaccine may represent a new, competent tool for next-generation personalized cancer vaccination.
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
Theranostics
·
2025
·Vol. 15
·期 10
·4481
·
IF 13.3
Yupeng Sun,Rui Li,Yike Cai,Yan Liu,Peiyuan Wang,Ming Wu,Xiaolong Zhang,Naishun Liao,Cuilin Zhang,Aixian Zheng,Haipo Xu,Rui Zeng,Yongyi Zeng,Xiaolong Liu
Tumor-infiltrating CD8 + T cells and programmed death-1 (PD1) levels are critical indicators for tumor immunophenotyping and therapeutic decision-making. Noninvasive optical imaging in the second near infrared window (NIR-II) is particularly well-suited for investigating the biological processes within tumors in live mammals, thanks to its deep-tissue penetration and superior spatiotemporal resolution. However, in vivo NIR-II imaging has primarily been restricted to a single probe at a time. Methods: Herein, we developed a two-plex NIR-II molecular imaging method utilizing the non-overlapping fluorescence emission of indocyanine green (ICG) in the NIR-IIa window (1000-1200 nm) and PbS/CdS core-shell quantum dots (QDs) in the NIR-IIb window (1500-1700 nm). By integrating PD1 aptamer-labeled ICG (ICG-Apt-PD1, targeting PD1) and CD8 aptamer-labeled QDs (QDs@Apt-CD8, targeting CD8 + T cells), our two-plex NIR-II molecular imaging enabled simultaneous and noninvasive monitoring of the number of CD8 + T cells and PD1 levels in tumors. Results: QDs@Apt-CD8 demonstrated the excellent ability for in vivo imaging of tumor infiltrating CD8 + T cells, owing to its strong NIR-IIb luminescence and the high selectivity and specificity. This two-plex in vivo molecular imaging allowed for dynamic monitoring for PD1 levels and the number of CD8 + T cells in tumors. We observed the heterogeneous bio-distributions of PD1 and CD8 + T cells across different tumor types and revealed the tumor immunophenotypes. Moreover, our findings indicated that the low PD1 and high CD8 + T cells levels in tumors predicted a better anti-tumor effect. Conclusions: Such in vivo noninvasive NIR-II molecular imaging would complement ex vivo biopsy-based diagnostic techniques, and it could contribute to developing an in vivo tumor immune-scoring algorithm to offer a more precise prediction for immunotherapeutic response.
研究领域:
生物医学工程
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肿瘤免疫学
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分子影像学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2023
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Arthritis & Rheumatology
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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
Cancers
·
2022
·Vol. 14
·期 23
·5951
·
IF 6.575
Qiyi Yi,Youguang Pu,Fengmei Chao,Po Bian,Lei Lv
Simple SummaryACAP1 plays a key role in endocytic recycling, which is essential for the normal function of lymphocytes. This study aimed to assess the expression and function of ACAP1 in lymphocytes. In this study, we revealed that ACAP1 is expressed primarily in lymphocytes and is necessary for the normal function of lymphocytes. Its expression is regulated by promoter DNA methylation and the transcription factor SPI1. ACAP1 levels positively correlate with the infiltrating levels of tumor-infiltrating lymphocytes (TILs) across a broad range of solid cancer types. Moreover, ACAP1 deficiency is associated with poor prognosis and immunotherapeutic response in multiple cancer types treated with immunotherapy. Thus, this study demonstrates that ACAP1 is a novel lymphocyte marker. We propose a widely applicable indicator to predict response to immunotherapy that may guide cancer patient stratification for appropriate therapy.AbstractBackground: ACAP1 plays a key role in endocytic recycling, which is essential for the normal function of lymphocytes. However, the expression and function of ACAP1 in lymphocytes have rarely been studied. Methods: Large-scale genomic data, including multiple bulk RNA-sequencing datasets, single-cell sequencing datasets, and immunotherapy cohorts, were exploited to comprehensively characterize ACAP1 expression, regulation, and function. Gene set enrichment analysis (GSEA) was used to uncover the pathways associated with ACAP1 expression. Eight algorithms, including TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, xCELL, MCPCOUNTER, EPIC, and TIDE, were applied to estimate the infiltrating level of immune cells. Western blotting, qPCR, and ChIP-PCR were used to validate the findings from bioinformatic analyses. A T-cell co-culture killing assay was used to investigate the function of ACAP1 in lymphocytes. Results: ACAP1 was highly expressed in immune-related tissues and cells and minimally in other tissues. Moreover, single-cell sequencing analysis in tumor samples revealed that ACAP1 is expressed primarily in tumor-infiltrating lymphocytes (TILs), including T, B, and NK cells. ACAP1 expression is negatively regulated by promoter DNA methylation, with its promoter hypo-methylated in immune cells but hyper-methylated in other cells. Furthermore, SPI1 binds to the ACAP1 promoter and positively regulates its expression in immune cells. ACAP1 levels positively correlate with the infiltrating levels of TILs, especially CD8+ T cells, across a broad range of solid cancer types. ACAP1 deficiency is associated with poor prognosis and immunotherapeutic response in multiple cancer types treated with checkpoint blockade therapy (ICT). Functionally, the depletion of ACAP1 by RNA interference significantly impairs the T cell-mediated killing of tumor cells. Conclusions: Our study demonstrates that ACAP1 is essential for the normal function of TILs, and its deficiency indicates an immunologically “cold” status of tumors that are resistant to ICT.Keywords:ACAP1;tumor-infiltrating lymphocytes (TILs);immune checkpoint blockade therapy (ICT);cancer immunotherapy;CD8+ T cells
研究领域:
肿瘤学
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免疫学
·
癌症生物学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2023
·
IF 29
Jie Cheng,Jinxin Yan,Ying Liu,Jiangzhou Shi,Haoyu Wang,Hanyang Zhou,Yinglin Zhou,Tongcun Zhang,Lina Zhao,Xianbin Meng,Haipeng Gong,Xinxiang Zhang,Haichuan Zhu,Peng Jiang
Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8 + T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8 + T cells, resulting in suppressed CD8 + T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8 + T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
代谢学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Heng Wang,Guojiang Zhang,Cai Zhao,Youan Xue,Di Zhu,Yan Chang
While interferon-alpha (IFN-α) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-α resistance and improve its efficacy. RAR-related orphan receptor gamma t (RORγt) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the RORγt agonist-LYC-55716 and IFN-α significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8 + T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8 + T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy
研究领域:
肿瘤免疫学
·
肝脏疾病
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分子生物学
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药物开发
✓ 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）