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

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 More importantly, our unpublished studies further revealed that among different CD8+ T cell subpopulations, effector memory (TEM) and terminally differentiated effector (TTE) CD8+ T cells are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.
项目摘要 最近,我们有了一个新的令人兴奋的发现,肿瘤或肿瘤微环境(TME)导致T- 细胞功能障碍和死亡。我们分析了肿瘤的sc-RNA-seq数据, 黑色素瘤患者的浸润性T细胞,并发现肿瘤浸润性CD 8 + T细胞具有显著的 与血液CD 8 + T相比,与脂质过氧化和铁凋亡相关的基因表达增加 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 CD 8 + T细胞亚群、效应记忆(TEM)和终末分化效应(TTE)CD 8 + T细胞是 对肿瘤引起的铁凋亡更敏感。我们检测了来自骨骼的肿瘤浸润性CD 8 + T细胞, 多发性骨髓瘤患者的骨髓(BM;肿瘤床)。通过将T细胞分为幼稚、TTE或TEM 基于它们的CCR 7和CD 45 RA表达,我们发现TEM和TTE CD 8 + T细胞表达 更高水平的脂质过氧化和铁蛋白沉积相关基因,对肿瘤诱导的 与幼稚的CD 8 + T细胞相比,尽管它们表达类似水平的CD 36,但它们的铁凋亡率仍然很高。同样在 在小鼠黑色素瘤和MM模型中,增加的铁凋亡主要发生在肿瘤浸润性CD 8 + TEM中, TTE细胞,但与小肿瘤小鼠相比,大肿瘤小鼠的幼稚CD 8 + T细胞中没有 负担我们的离体研究证实,CD 8 + TEM和TTE细胞对肿瘤或FA-1细胞更敏感。 诱导的铁凋亡比幼稚T细胞和他们的细胞毒性细胞因子,如IFNγ和TNFα的生产, 压抑为了阐明潜在的机制,使用RNA-seq,并显示CD 8 + TEM和TTE 细胞表达的2,4-二烯酰辅酶A还原酶1(DECR 1)水平显著较低,DECR 1是一种限速酶, 多不饱和脂肪酸(PUFA)β-氧化,与幼稚CD 8 + T细胞相比。DECR 1的敲低(KD), 幼稚的CD 8 + T细胞导致PUFA表达增加和过氧化物酶体功能障碍, 它们对肿瘤或FA诱导的铁凋亡的影响比对照T细胞要大。基于这些新发现,我们假设 CD 8 + TEM和TTE细胞,由于摄取更多的FA和减少DECR 1和PUFA的表达, 氧化,对肿瘤/TME诱导的铁凋亡敏感,抑制TEM和TTE细胞铁凋亡可能 有效提高免疫疗法对癌症患者的治疗效果。目标1将决定 TME中CD 8 + TEM和TTE细胞中肿瘤或FA诱导的铁凋亡的潜在机制。目标2将阐明 Fas在肿瘤和TME中蓄积及诱导CD 8+细胞脂质过氧化作用及其机制 TEM和TTE T细胞和Aim 3将抑制CD 8 + TEM和TTE细胞的铁凋亡,以增强抗癌疗效 免疫疗法实现这些目标将使我们深入了解这些机制, 肿瘤和TME如何诱导T细胞脂质过氧化以及铁凋亡如何介导T细胞凋亡 代谢紊乱和死亡了解这些机制非常重要, 帮助我们开发新的治疗方法,以靶向T细胞脂质代谢和TME, 提高癌症免疫治疗的疗效。

项目成果

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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:
    $ 48.45万
  • 项目类别:
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
  • 批准号:
    10673683
  • 财政年份:
    2019
  • 资助金额:
    $ 48.45万
  • 项目类别:
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
  • 批准号:
    10251255
  • 财政年份:
    2019
  • 资助金额:
    $ 48.45万
  • 项目类别:
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
  • 批准号:
    10456222
  • 财政年份:
    2019
  • 资助金额:
    $ 48.45万
  • 项目类别:
Role of MIF in myeloma bone homing and drug response
MIF 在骨髓瘤骨归巢和药物反应中的作用
  • 批准号:
    9211149
  • 财政年份:
    2017
  • 资助金额:
    $ 48.45万
  • 项目类别:
Targeting macrophages to sensitize myeloma to immune checkpoint blockade
靶向巨噬细胞使骨髓瘤对免疫检查点阻断敏感
  • 批准号:
    9634041
  • 财政年份:
    2017
  • 资助金额:
    $ 48.45万
  • 项目类别:
Targeting macrophages to sensitize myeloma to immune checkpoint blockade
靶向巨噬细胞使骨髓瘤对免疫检查点阻断敏感
  • 批准号:
    10091406
  • 财政年份:
    2017
  • 资助金额:
    $ 48.45万
  • 项目类别:
Role of MIF in myeloma bone homing and drug response
MIF 在骨髓瘤骨归巢和药物反应中的作用
  • 批准号:
    10078263
  • 财政年份:
    2017
  • 资助金额:
    $ 48.45万
  • 项目类别:
Targeting macrophages to sensitize myeloma to immune checkpoint blockade
靶向巨噬细胞使骨髓瘤对免疫检查点阻断敏感
  • 批准号:
    9283894
  • 财政年份:
    2017
  • 资助金额:
    $ 48.45万
  • 项目类别:
A novel T-cell subset able to kill relapsed cancers
一种能够杀死复发癌症的新型 T 细胞亚群
  • 批准号:
    9291443
  • 财政年份:
    2016
  • 资助金额:
    $ 48.45万
  • 项目类别:

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