Chronic/latent viral infections modulate the function of cytotoxic T cells and natural killer cells with antitumor activity
慢性/潜伏病毒感染调节细胞毒性 T 细胞和自然杀伤细胞的功能,具有抗肿瘤活性
基本信息
- 批准号:513832316
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Studies reported an increased risk of cancers among patients with persistent viral infections, especially retroviruses and herpes virus infections. However, the influence of chronic/latent viral infections on antitumor immunity has so far been poorly investigated. We will study the role of cytotoxic T cells and natural killer (NK) cells because such cells are strongly activated by many viral infections and are essential for antitumor immunity in most cancer models. Chronic Friend retrovirus (FV) and latent murine cytomegalovirus (MCMV) or herpes simplex virus (HSV) infections induce cytotoxic T-cell and NK cell responses that contribute to the control of these persistent viruses in mice. Because of viral persistence, these cytotoxic CD4 T and NK effector cells are continuously activated, but it remains unclear whether they are beneficial or detrimental for tumor immune surveillance. Using the FV model, we demonstrated that transplanted FBL-3 tumor cells can be rejected by cytotoxic T cells in naïve mice but grow progressively in chronically FV-infected mice. Thus, the chronic infection interferes with the cytotoxic T-cell response, which is explained by the massive expansion of suppressive regulatory T cells (Treg). Also, HSV infection induces a profound expansion of Tregs. Thus, we will analyze the antitumor activity of virus-induced CD4 T and NK cells in persistently FV- and HSV-infected mice and will define strategies enhancing their effector functions after tumor challenge. In sharp contrast, CMV infection does not expand Tregs but is characterized by one of the strongest activations of cytotoxic T and NK cells known in virus infections. This strong cytotoxic response can contribute to antitumor immunity and tumor cell rejection. We will carefully compare these detrimental and beneficial effects of different persistent viral infections at the cellular and molecular level in mouse models. To determine the clinical significance of our findings from mouse models, we will analyze the effect of latent human CMV and HSV-1 infections on cytotoxic antitumor T- and NK-cell responses among melanoma patients. We will determine whether CMV/HSV-specific CD4 T cells and virus-induced memory-like NK cells contribute to melanoma cell killing or whether the induction of Tregs restricts melanoma-reactive T- and NK-cell responses of melanoma patients. We will study the role of latent CMV and HSV infection in clinical responses under immune checkpoint blocking therapy and therapy-associated immune-related adverse events. Thus, we plan to dissect immunological mechanisms involved in the modulation of tumor immunity that are induced by persistent infections.
研究报告称,持续病毒感染,特别是逆转录病毒和疱疹病毒感染的患者患癌症的风险增加。然而,迄今为止,慢性/潜伏病毒感染对抗肿瘤免疫的影响研究甚少。我们将研究细胞毒性T细胞和自然杀伤(NK)细胞的作用,因为这些细胞被许多病毒感染强烈激活,并且在大多数癌症模型中对抗肿瘤免疫至关重要。慢性Friend逆转录病毒(FV)和潜伏小鼠巨细胞病毒(MCMV)或单纯疱疹病毒(HSV)感染诱导细胞毒性t细胞和NK细胞反应,有助于控制小鼠体内这些持续性病毒。由于病毒的持续存在,这些细胞毒性CD4 T和NK效应细胞不断被激活,但它们对肿瘤免疫监视是有益还是有害尚不清楚。通过FV模型,我们证明了移植的FBL-3肿瘤细胞在naïve小鼠中可以被细胞毒性T细胞排斥,但在慢性FV感染小鼠中可以逐渐生长。因此,慢性感染干扰了细胞毒性T细胞反应,这可以用抑制性调节性T细胞(Treg)的大量扩增来解释。此外,HSV感染诱导treg的大量扩增。因此,我们将分析病毒诱导的CD4 T和NK细胞在持续FV和hsv感染小鼠中的抗肿瘤活性,并确定在肿瘤攻击后增强其效应功能的策略。与此形成鲜明对比的是,巨细胞病毒感染不会扩增Tregs,但其特征是在病毒感染中已知的细胞毒性T和NK细胞的最强激活之一。这种强烈的细胞毒性反应有助于抗肿瘤免疫和肿瘤细胞排斥。我们将在小鼠模型的细胞和分子水平上仔细比较不同持续性病毒感染的这些有害和有益影响。为了确定小鼠模型研究结果的临床意义,我们将分析潜伏的人类巨细胞病毒和HSV-1感染对黑色素瘤患者细胞毒性抗肿瘤T细胞和nk细胞反应的影响。我们将确定CMV/ hsv特异性CD4 T细胞和病毒诱导的记忆样NK细胞是否有助于黑色素瘤细胞杀伤,或者Tregs的诱导是否限制黑色素瘤患者的黑色素瘤反应性T细胞和NK细胞反应。我们将研究潜伏CMV和HSV感染在免疫检查点阻断治疗和治疗相关免疫相关不良事件下的临床反应中的作用。因此,我们计划剖析由持续感染诱导的肿瘤免疫调节所涉及的免疫学机制。
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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Professor Dr. Ulf Dittmer其他文献
Professor Dr. Ulf Dittmer的其他文献
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{{ truncateString('Professor Dr. Ulf Dittmer', 18)}}的其他基金
Defining the cytotoxic T cell response in COVID-19 patients
定义 COVID-19 患者的细胞毒性 T 细胞反应
- 批准号:
458632721 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Research Grants
Virus-induced regulatory T cells in retroviral infection: new targets for immunotherapy of chronic infectious diseases.
逆转录病毒感染中病毒诱导的调节性T细胞:慢性传染病免疫治疗的新靶点。
- 批准号:
406041574 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Research Grants
Regulation of the induction of IFNα subtypes during HIV infection
HIV 感染期间 IFNα 亚型诱导的调节
- 批准号:
318291924 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Priority Programmes
Complement and regulatory T cells:The effect of complement on regulatory T cell responses in a mouse retrovirus model.
补体和调节性 T 细胞:补体对小鼠逆转录病毒模型中调节性 T 细胞反应的影响。
- 批准号:
282999617 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Research Grants
Recruitment and functional activity of tumor-infiltrating CD8+ cytotoxic T cells and CD4+ regulatory T cells
肿瘤浸润 CD8 细胞毒性 T 细胞和 CD4 调节性 T 细胞的募集和功能活性
- 批准号:
175696446 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Research Grants
Virus-induced regulatory T cells in retroviral infection: new targets for immunotherapy of chronic infectious diseases
逆转录病毒感染中病毒诱导的调节性T细胞:慢性传染病免疫治疗的新靶点
- 批准号:
5441032 - 财政年份:2005
- 资助金额:
-- - 项目类别:
Research Grants
Verwendung Virusantigen-beladener Dendritischer Zellen zur Prävention und Therapie von Retrovirus-induzierten Leukämien
负载病毒抗原的树突状细胞用于预防和治疗逆转录病毒诱导的白血病的用途
- 批准号:
5353674 - 财政年份:2002
- 资助金额:
-- - 项目类别:
Research Grants
Die Rolle von Virus-infizierten Dendritischen Zellen bei der Induktion einer Retrovirus-induzierten Immunsuppression
病毒感染的树突状细胞在诱导逆转录病毒诱导的免疫抑制中的作用
- 批准号:
5306434 - 财政年份:2001
- 资助金额:
-- - 项目类别:
Research Grants
Die Rolle von Cytokinen bei der Immunität und Pathogenese von Retrovirusinfektionen
细胞因子在免疫和逆转录病毒感染发病机制中的作用
- 批准号:
5223344 - 财政年份:1999
- 资助金额:
-- - 项目类别:
Research Grants
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