Role of lipid metabolism in CD8+ T cell ferroptosis
脂质代谢在 CD8 T 细胞铁死亡中的作用
基本信息
- 批准号:10792062
- 负责人:
- 金额:$ 48.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-19 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive Cell TransfersBedsBloodBone MarrowCD36 geneCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCell physiologyCellsCellular Metabolic ProcessCessation of lifeClinicalCoenzyme ACytotoxic T-LymphocytesDataEnzymesFatty AcidsFunctional disorderGene ExpressionGenesImmunotherapyImpairmentIn complete remissionIndividualInfiltrationInterferon Type IILipid PeroxidationMalignant NeoplasmsMediatingMelanoma CellMemoryMetabolicMethodsModelingMultiple MyelomaMusOxidoreductasePatientsPolyunsaturated Fatty AcidsProductionPrognosisPublicationsReportingRoleT-LymphocyteTNF geneTestingTreatment EfficacyTumor Burdencancer immunotherapycancer infiltrating T cellscomparison controlcytokinecytotoxiccytotoxic CD8 T cellseffector T cellfatty acid oxidationimmune checkpoint blockadeimprovedindividual patientknock-downlipid metabolismmelanomanew therapeutic targetnovelnovel therapeutic interventionoxidationprogramsresponsesingle-cell RNA sequencingsuccesstranscriptome sequencingtumortumor microenvironmentuptake
项目摘要
PROJECT SUMMARY
Recently, we made a novel and exciting discovery that tumors or the tumor microenvironment (TME) cause T-
cell dysfunction and death by inducing ferroptosis in T cells. We analyzed the sc-RNA-seq data of tumor-
infiltrating T cells from melanoma patients and discovered that tumor-infiltrating CD8+ T cells had significantly
increased expressions of genes associated with lipid peroxidation and ferroptosis compared to blood CD8+ T
cells from healthy individuals. More importantly, our unpublished studies further revealed that among different
CD8+ T cell subpopulations, effector memory (TEM) and terminally differentiated effector (TTE) CD8+ T cells are
more sensitive to tumor-induced ferroptosis. We examined tumor-infiltrating CD8+ T cells from the bone
marrow (BM; tumor bed) of patients with multiple myeloma. By separating the T cells into naïve, TTE or TEM
cells based on their expression of CCR7 and CD45RA, we found that TEM and TTE CD8+ T cells expressed
higher levels of lipid peroxidation- and ferroptosis-associated genes and were more sensitive to tumor-induced
ferroptosis compared to naïve CD8+ T cells although they expressed similar levels of CD36. Similarly, in
mouse melanoma and MM models, increased ferroptosis mainly occurred in tumor-infiltrating CD8+ TEM and
TTE cells but not in naïve CD8+ T cells from mice with large tumor burdens compared to those with small tumor
burdens. Our ex vivo studies confirmed that CD8+ TEM and TTE cells were more sensitive to tumor- or FA-
induced ferroptosis than naïve T cells and their production of cytotoxic cytokines such as IFNγ and TNFα was
inhibited. To elucidate the underlying mechanisms, RNA-seq was used and showed that CD8+ TEM and TTE
cells expressed a significantly lower level of 2,4-dienoyl-CoA reductase 1 (DECR1), a rate-limiting enzyme for
polyunsaturated fatty acid (PUFA) β-oxidation, compared to naïve CD8+ T cells. Knockdown (KD) of DECR1 in
naïve CD8+ T cells resulted in an increased PUFA expression and peroxisomal dysfunction and sensitized
them to tumor- or FA-induced ferroptosis than control T cells. Based on these novel findings, we hypothesize
that CD8+ TEM and TTE cells, due to uptake of more FAs and reduced expression of DECR1 and PUFA
oxidation, are sensitive to tumor/TME-induced ferroptosis, and inhibiting TEM and TTE cell ferroptosis may
effectively enhance the therapeutic efficacy of immunotherapy in cancer patients. Aim 1 will determine the
mechanism underlying tumor- or FA-induced ferroptosis in CD8+ TEM and TTE cells in TME. Aim 2 will elucidate
the role and mechanisms of tumor and TME accumulation of FAs and induction of lipid peroxidation in CD8+
TEM and TTE T cells and Aim 3 will inhibit CD8+ TEM and TTE cell ferroptosis to enhance the efficacy of cancer
immunotherapies. Accomplishing these aims will provide us with in-depth understanding of the mechanisms
underlying how tumors and the TME induce T cell lipid peroxidation and how ferroptosis mediates T cell
metabolic malfunction and death. Understanding these mechanisms is extremely important and will greatly
assist us in developing novel therapeutic approaches to target T cell lipid metabolism and TME to significantly
improve the efficacy of cancer immunotherapy.
项目概要
最近,我们有了一个令人兴奋的新发现,即肿瘤或肿瘤微环境 (TME) 会导致 T-
通过诱导 T 细胞铁死亡而导致细胞功能障碍和死亡。我们分析了肿瘤的 sc-RNA-seq 数据
研究人员对来自黑色素瘤患者的浸润性 T 细胞进行了研究,发现肿瘤浸润性 CD8+ T 细胞显着
与血液 CD8+ T 相比,与脂质过氧化和铁死亡相关的基因表达增加
来自健康个体的细胞。更重要的是,我们未发表的研究进一步表明,在不同的
CD8+ T 细胞亚群、效应记忆 (TEM) 和终末分化效应 (TTE) CD8+ T 细胞
对肿瘤引起的铁死亡更敏感。我们检查了来自骨骼的肿瘤浸润性 CD8+ T 细胞
多发性骨髓瘤患者的骨髓(BM;瘤床)。通过将 T 细胞分为 naïve、TTE 或 TEM
根据细胞中 CCR7 和 CD45RA 的表达,我们发现 TEM 和 TTE CD8+ T 细胞表达
脂质过氧化和铁死亡相关基因水平较高,并且对肿瘤诱导的疾病更敏感
与幼稚 CD8+ T 细胞相比,铁死亡,尽管它们表达的 CD36 水平相似。同样,在
小鼠黑色素瘤和 MM 模型中,铁死亡增加主要发生在肿瘤浸润性 CD8+ TEM 和
TTE 细胞,但不存在于来自肿瘤负荷较大的小鼠(与肿瘤较小的小鼠相比)的初始 CD8+ T 细胞中
负担。我们的离体研究证实 CD8+ TEM 和 TTE 细胞对肿瘤或 FA- 更敏感
与幼稚 T 细胞相比,它们诱导铁死亡,并且它们产生细胞毒性细胞因子(例如 IFNγ 和 TNFα)
抑制。为了阐明潜在机制,使用 RNA-seq 并显示 CD8+ TEM 和 TTE
细胞表达的 2,4-二烯酰辅酶 A 还原酶 1 (DECR1) 水平显着降低,这是一种限速酶。
与初始 CD8+ T 细胞相比,多不饱和脂肪酸 (PUFA) β-氧化。 DECR1 的敲低 (KD)
初始 CD8+ T 细胞导致 PUFA 表达增加和过氧化物酶体功能障碍并致敏
与对照 T 细胞相比,它们更容易导致肿瘤或 FA 诱导的铁死亡。基于这些新发现,我们假设
CD8+ TEM 和 TTE 细胞,由于摄取更多 FA 以及 DECR1 和 PUFA 表达减少
氧化,对肿瘤/TME 诱导的铁死亡敏感,抑制 TEM 和 TTE 细胞铁死亡可能
有效增强癌症患者免疫治疗的治疗效果。目标 1 将确定
TME 中 CD8+ TEM 和 TTE 细胞中肿瘤或 FA 诱导的铁死亡的机制。目标 2 将阐明
肿瘤和 TME 中 FA 积累和诱导 CD8+ 脂质过氧化的作用和机制
TEM和TTE T细胞和Aim 3将抑制CD8+ TEM和TTE细胞铁死亡以增强癌症功效
免疫疗法。实现这些目标将使我们对机制有深入的了解
肿瘤和 TME 如何诱导 T 细胞脂质过氧化以及铁死亡如何介导 T 细胞的基础
代谢功能障碍和死亡。了解这些机制极其重要,并且将极大地促进
协助我们开发针对 T 细胞脂质代谢和 TME 的新型治疗方法,以显着改善
提高癌症免疫治疗的疗效。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Qing Yi其他文献
Qing Yi的其他文献
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{{ truncateString('Qing Yi', 18)}}的其他基金
Novel mechanism of induction of tumor pyroptosis by IL-9-secreting Tc9 cells
分泌IL-9的Tc9细胞诱导肿瘤焦亡的新机制
- 批准号:
10704861 - 财政年份:2023
- 资助金额:
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Role of tumor microenvironment-derived cholesterol in CD8+ T-cell exhaustion
肿瘤微环境衍生的胆固醇在 CD8 T 细胞耗竭中的作用
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