Cell Reports Medicine
·
2023
·
IF 14.3
Yutong Wu,Hongbo Ai,Yuhang Xi,Jiulin Tan,Ying Qu,Jianzhong Xu,Fei Luo,Ce Dou
Summary The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8 + T cell infiltrations and a higher survival rate. We uncover that the membranous Siglec15 on osteoclast-derived ABs binds with sialylated Toll-like receptor 2 (TLR2) and blocks downstream co-stimulatory signaling, leading to the inhibition of naive CD8 + T cell activation. In addition, our study shows that treatment with Siglec15 neutralizing antibodies significantly reduces the incidence of secondary metastases and improves the survival rate of mice with advanced breast cancer bone metastasis. Our findings reveal the immunosuppressive function of osteoclast-derived ABs in the bone-tumor niche and demonstrate the potential of Siglec15 as a common target for anti-resorption and immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
细胞生物学
·
癌症转移
✓ 已验证
DOI
PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-12
·
IF 5.9
Wang You-Yuan,Zhen Cheng,Hu Wei,Huang Hui-Huang,Li Yan-Jun,Zhou Ming-Ju,Li Jing,Fu Yu-Long,Zhang Peng,Li Xiao-Yu,Yang Tao,Song Jin-Wen,Fan Xing,Zou Jun,Meng Si-Run,Qin Ya-Qin,Jiao Yan-Mei,Xu Ruonan,Zhang Ji-Yuan,Zhou Chun-Bao,Yuan Jin-Hong,Huang Lei,Shi Ming,Cheng Liang,Wang Fu-Sheng,Zhang Chao
CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.
研究领域:
免疫学
·
病毒学
·
代谢学
·
HIV/AIDS研究
✓ 已验证
产品关联
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
·
免疫学
·
分子生物学
·
癌症免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Jingjing Cong,Pianpian Liu,Zili Han,Wei Ying,Chaoliang Li,Yifei Yang,Shuling Wang,Jianbo Yang,Fei Cao,Juntao Shen,Yu Zeng,Yu Bai,Congzhao Zhou,Lilin Ye,Rongbin Zhou,Chunjun Guo,Chunlei Cang,Dennis L. Kasper,Xinyang Song,Lei Dai,Linfeng Sun,Wen Pan,Shu Zhu
Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8 + T cell effector function. Mechanistically, DCA suppressed CD8 + T cell responses by targeting plasma membrane Ca 2+ ATPase (PMCA) to inhibit Ca 2+ -nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8 + T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8 + T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8 + T cell response in CRC, suggesting potential directions for anti-tumor therapy.
研究领域:
肿瘤学
·
免疫学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2024
·Vol. 12
·期 10
·e009416
·
IF 10.3
Hua Huang,Yuwen Pan,Qiuwen Mai,Chunyu Zhang,Qiqiao Du,Yuandong Liao,Shuhang Qin,Yili Chen,Jiaming Huang,Jie Li,Tianyu Liu,Qiaojian Zou,Yijia Zhou,Li Yuan,Wei Wang,Yanchun Liang,Chao Yun Pan,Junxiu Liu,Shuzhong Yao
Background Cervical cancer remains a global health challenge. The identification of new immunotherapeutic targets may provide a promising platform for advancing cervical cancer treatment. Objective This study aims to investigate the role of CUB domain-containing protein 1 (CDCP1) in cervical cancer progression and evaluate its potential as a therapeutic target. Methods We performed comprehensive analyses using patient cohorts and preclinical models to examine the association between CDCP1 expression and cervical cancer prognosis. Then in immunodeficient and immunocompetent mouse models, we further investigated the impact of CDCP1 on the tumor immune microenvironment, focusing on its effects on tumor-infiltrating T cells, including cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Mechanistic studies were performed to elucidate the pathways involved in CDCP1-mediated immune modulation, in particular its interaction with the T cell receptor CD6 and the activation of the JAK-STAT signaling pathway. Results Our results show that CDCP1 overexpression is associated with poor prognosis and T cell infliction in cervical cancer. Specifically, it affects the activity of CTLs and Tregs. Mechanistically, CDCP1 binds to CD6 and inhibits the JAK-STAT pathway of T cells. The study further demonstrates that targeting CDCP1 with the inhibitor 8-prenylnaringenin (8PN) effectively suppresses tumor growth in vivo and enhances antitumor immunity. Conclusions CDCP1 plays a critical role in cervical cancer progression by modulating the tumor immune microenvironment. Targeting CDCP1 offers a promising therapeutic strategy to improve the outcome of patients with cervical cancer.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
·
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
·
免疫学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
Cell Metabolism
·
2025
·
IF 30.9
Tiezhu Shi,Jialiang Shao,Yufeng Ding,Hong Tang,Xiangyin Tan,Sisi Zhou,Shaoqing Yu,Xiang Wang,Guanzhen Yu,Ninghan Feng,Xiongjun Wang
Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using in vivo metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8 + T cell cytotoxicity. Mechanistically, CD8 + T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8 + T cell response by promoting Xu5P-responsive progenitor-like SLC35E2 + CD8 + exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the Tcf7 promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8 + T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.
研究领域:
癌症生物学
·
免疫学
·
代谢工程
·
分子生物学
·
遗传学
·
肿瘤免疫学
·
营养科学
·
细胞信号传导
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
He Ren,Jiexin Li,Gengqi Liu,Yaping Sun,Xingyue Yang,Zhen Jiang,Jingyu Zhang,Jonathan F. Lovell,Yumiao Zhang
The development of nanocarriers capable of codelivering antigens and immune-activating adjuvants is an emerging area of research and is relevant for cancer vaccines that target induction of antigen-specific CD8+ T-cell responses. Here, we report a system for delivery of short peptide antigens to dendritic cells for strong cellular immune responses, based on block copolymers chemically modified with a hydrophobic and self-immolative linker. After modification, micelles effectively and reversibly capture antigens and adjuvants via a covalent bond within several minutes in an aqueous solution. After uptake in antigen presenting cells, the polymer disulfide bond is cleaved by intracellular glutathione, leading to release of pristine antigens, along with the upregulated expression of costimulatory molecules. The induced antigen-specific CD8+ T cells have strong tumor cell killing efficacy in the murine B16OVA and human papilloma virus-E6/E7 subcutaneous and lung metastasis tumor models. In addition, delivery to lymph nodes can be imaged to visualize vaccine trafficking. Taken together, multifunctional self-immolative micelles represent a versatile class of a vaccine delivery system for the generation of a cellular immune response that warrants further exploration as a component of cancer immunotherapy.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2024
·
IF 5.8
Pan Li,Zihe Zhai,Jiawen Fang,Ruo Wang,Weiqi Li,Beiduo Wang,Jinglei Wang,Jiaqi Zhu,Feng Bing,Qiaoling Pan,ChangYou Gao,ShaoHong Lu
Together, tumor and virus-specific tissue-resident CD8+ memory T cells (TRMs) of hepatocellular carcinoma (HCC) patients with Hepatitis B virus (HBV) infection can provide rapid frontline immune surveillance. The quantity and activity of CD8+ TRMs were correlated with the relapse-free survival of patients with improved health. However, HBV-specific CD8+ TRMs have a more exhausted phenotype and respond more actively under anti-PDL1 or PD1 treatment of HBV+HCC patients. Vaccination strategies that induce a strong and sustained CD8+ TRMs response are quite promising. Herein, a biodegradable poly(D,L-lactide-co-glycolide) microsphere and nanosphere particle (PLGA N.M.P) delivery system co-assembled by anti-PD1 antibodies (aPD1) and loaded with ovalbumin (OVA-aPD1 N.M.P) was fabricated and characterized for size (200 nm and 1 μm diameter), charge (−15 mV), and loading efficiencies of OVA (238 μg mg−1 particles) and aPD1 (40 μg mg−1 particles). OVA-aPD1 N.M.P could stimulate the maturation of BMDCs and enhance the antigen uptake and presentation by 2-fold compared to free OVA. The nanoparticles also induced the activation of macrophages (RAW 264.7) to produce a high level of cytokines, including TNF-α, IL-6 and IL-10. In vivo stimulation of mice using OVA-aPD1 N.M.P robustly enhanced IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and the secretion of IgG and IgG2a/IgG1 antibodies. OVA-aPD1 N.M.P delivered OVA to increase the activation and proliferation of OVA-specific CD8+ TRMs, and its combination with anti-PD1 antibodies promoted complete tumor rejection by the reversal of tumor-infiltrating CD8+ T cell exhaustion. Thus, PLGA N.M.P could induce a strong CD8+ TRMs response, further highlighting its therapeutic potential in enhancing an antitumor immune response.
研究领域:
癌症免疫学
·
药学
·
免疫治疗
·
纳米技术
·
肿瘤生物学
✓ 已验证
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
·
分子生物学
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Ting Yang,Zihan Liu,Zixuan Fu,Xiaojie Zhang,Yongjin Cao,Qiangwei Liang,Jiale Miao,Hao Yang,Tong Zhang,Jing Hei,Weiqing Ni,Yanhua Liu
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer (TNBC) therapy. However, the ferroptosis accompanied with down-regulation of glutathione peroxidase 4 (GPX4) lead to CD36-mediated tumor-infiltrating CD8 + T cells uptaking fatty acids, resulting in the negative action on immunotherapeutic efficacy. Herein, the albumin nanoparticles, abbreviated as LHS NPs, were designed by co-assembly of hemin, linoleic acid-cystamine, and a CD36 inhibitor sulfosuccinimide oleate, to bi-directionally manipulated ferroptosis in tumor and CD8 + T cells for TNBC therapy. LHS NPs exerted more efficient reactive oxygen species generation, glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes, which amplified the positive action on ferroptosis in tumor cells. Meanwhile, LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8 + T cells, thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death, proliferation of CD4 + CD8 + T cells and natural killer cells, alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and repolarization of the M2- to M1-phenotype tumor-associated macrophages. Thus, LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lung metastasis of 4T1-tumor mice. Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8 + T cells on TNBC chemoimmunotherapy.
研究领域:
癌症治疗
·
纳米医学
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Changwei Zhang,Qinghui Cao,Yuanyu Li,Juan Lu,Sidong Xiong,Yan Yue
The induction of a robust CD8 + T cell response is critical for the success of an antiviral vaccine. In this study, we incorporated a STING agonist (SA) 2′3’-cGAMP into a previously developed exosome-based CVB3 viral myocarditis vaccine (Exo-VP1) to enhance its ability to induce CD8 + T cell responses and immunoprotection. Our results showed that compared to free SA adjuvant, exosome-mediated co-delivery (Exo SA -VP1) significantly enhanced SA uptake by dendritic cells (DCs) and more potently stimulated DC maturation. Immunization of mice showed that the Exo SA -VP1 vaccine-induced higher levels of CVB3-specific T cell proliferation and cytotoxicity, significantly increased the percentage of IFN-γ + CD8 + rather than CD4 + T cells, effectively reduced cardiac viral loads, attenuated myocarditis and improved survival in mice compared to the previous Exo-VP1 vaccine. Further investigation showed that Exo SA -VP1 significantly increased both the percentage and antigen cross-presentation capacity of splenic CD8 + DCs. Depletion of these CD8 + DCs by cytochrome C administration nearly abolished the advantage of Exo SA -VP1 in dominantly inducing IFN-γ + CD8 + cytotoxic T lymphocyte (CTL) production in immunized mice. Taken together, our results demonstrated the potential of Exo SA -VP1 as a promising candidate for anti-CVB3 vaccines and provide insights into immune-enhancing strategies aiming at augmenting antigen cross-presentation by DCs and enhancing potent CTL responses.
研究领域:
免疫学
·
病毒学
·
药学
·
分子生物学
✓ 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）