Disparate suppression of naive effector and memory T cells in tumor-bearing hosts

荷瘤宿主中幼稚效应 T 细胞和记忆 T 细胞的不同抑制

• 批准号: 7537204
• 负责人: Jose Alejandro Guevara-Patino
• 金额: $ 17.27万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537204
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Antigens; Autoantigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cells; Chickens; Clinical; Data; Disease; Dominant-Negative Mutation; Excision; Failure; Genes; Goals; Immune; Immune response; Immunization; Immunotherapy; In Vitro; Malignant Neoplasms; Mediator of activation protein; Melanoma Cell; Membrane Microdomains; Memory; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Ovalbumin; Patients; Phosphoproteins; Predisposition; Primary Neoplasm; Resistance; Role; Signal Transduction; Staging; Suppressor-Effector T-Lymphocytes; T memory cell; T-Lymphocyte; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Immunity; Tyrosinase related protein-1; Vaccination; Vaccines; base; cancer therapy; conventional therapy; design; human TYRP1 protein; in vivo; melanocyte; melanoma; outcome forecast; response; tumor; tumor growth

DESCRIPTION (provided by applicant): Despite the sustained efforts of numerous groups to develop immune approaches for the treatment of cancer, thus far, the therapeutic responses have been disappointing. The reasons for this failure remain unknown. Thus, in the current study we propose to study the role of T-cell maturation stage in determining T-cell susceptibility to tumor-induced suppression by alterations in TGF-b susceptibility. Memory and effector CD8+ T cells are functionally more responsive than naive cells. Thus, we hypothesized that memory and effector T cells were less susceptible to tumor-induced suppression than naive cells. Paradoxically, we found that effector CD8+ T cells were considerably more susceptible to tumor-induced suppression than naive cells (90% vs. 30%). Our data suggest that adoptive transfer of in vitro activated effector CD8+ T cells may be ineffective due to increased CD8+ T-cell susceptibility to tumor-induced suppression. Regarding the mechanisms responsible for this disparate effect, we found that TGF-b was a key molecular mediator of suppression, and expression of transcriptional regulators of TGF-b signaling (Smad4 and TGF-bRII) correlated with T-cell status and susceptibility to suppression. Based on these observations, we propose the following hypothesis: CD8+ T-cell maturation status (naive, effector and memory) determines susceptibility to tumor-induced suppression, with effector and memory T cells being more susceptible to suppression than naive T cells, due to increased responsiveness to TGF-b. In order to evaluate antigen specific CD8+ T-cell responses, we will use CD8+ T cells from transgenic mice expressing a CD8+ TCR against gp100/pmel (a self antigen naturally expressed by normal melanocytes and melanoma cells) and a non-self antigen, chicken ovalbumin (OT-I). 1) We will examine the susceptibility of naive, effector and memory CD8+ T cells to TGF-b in vitro, and whether expression of TGF-bRII and Smads correlates with susceptibility to suppression. 2) We will evaluate the in vivo suppressive effect of tumor disseminated disease (early and established) on naive, effector and memory CD8+ T cells, and the effect of depleting suppressor cells or blocking TGF-b on naive, effector and memory CD8+ T-cell responses. 3) We will study whether interfering with TGF-b signaling in vivo in CD8+ T cells evenly rescues naive, effector and memory TCR transgenic CD8+ T cells from tumor-induced suppression. Narrative The results of T-cell based immune therapeutic approaches against cancer based on adoptive cell transfer and vaccination, thus far, have been disappointing for reasons that remain unknown. Thus, in the current study we propose to study the role of T-cell maturation stage (naive, effector and memory) in determining T-cell susceptibility to tumor-induced suppression by alterations in TGF-b susceptibility.

描述（由申请人提供）：尽管许多团体持续努力开发治疗癌症的免疫方法，但迄今为止，治疗反应令人失望。这次失败的原因仍然未知。因此，在当前的研究中，我们建议研究 T 细胞成熟阶段在通过 TGF-b 敏感性改变来确定 T 细胞对肿瘤诱导抑制的敏感性中的作用。记忆和效应 CD8+ T 细胞在功能上比初始细胞更敏感。因此，我们假设记忆 T 细胞和效应 T 细胞比初始细胞更不易受到肿瘤诱导的抑制的影响。矛盾的是，我们发现效应 CD8+ T 细胞比初始细胞更容易受到肿瘤诱导的抑制（90% vs. 30%）。我们的数据表明，由于 CD8+ T 细胞对肿瘤诱导的抑制的敏感性增加，体外激活的效应 CD8+ T 细胞的过继转移可能无效。关于造成这种不同效应的机制，我们发现 TGF-b 是抑制的关键分子介质，并且 TGF-b 信号转导转录调节因子（Smad4 和 TGF-bRII）的表达与 T 细胞状态和抑制易感性相关。基于这些观察，我们提出以下假设：CD8+ T 细胞成熟状态（初始、效应和记忆）决定了对肿瘤诱导抑制的易感性，效应和记忆 T 细胞比初始 T 细胞更容易受到抑制，这是由于增加对 TGF-b 的反应性。为了评估抗原特异性 CD8+ T 细胞反应，我们将使用来自表达针对 gp100/pmel（正常黑色素细胞和黑色素瘤细胞天然表达的自身抗原）的 CD8+ TCR 的转基因小鼠的 CD8+ T 细胞和非自身抗原鸡卵清蛋白（OT-I）。 1) 我们将在体外检查初始、效应和记忆 CD8+ T 细胞对 TGF-b 的敏感性，以及 TGF-bRII 和 Smads 的表达是否与抑制的敏感性相关。 2) 我们将评估肿瘤播散性疾病（早期和已建立）对幼稚、效应和记忆CD8+ T细胞的体内抑制作用，以及耗尽抑制细胞或阻断TGF-b对幼稚、效应和记忆CD8+ T-细胞的作用细胞反应。 3) 我们将研究体内干扰CD8+ T细胞中的TGF-b信号传导是否可以均匀地拯救幼稚、效应和记忆TCR转基因CD8+ T细胞免受肿瘤诱导的抑制。 叙述 迄今为止，基于过继细胞转移和疫苗接种的基于 T 细胞的癌症免疫治疗方法的结果令人失望，原因尚不清楚。因此，在本研究中，我们建议研究 T 细胞成熟阶段（幼稚期、效应期和记忆期）在通过 TGF-b 敏感性改变来确定 T 细胞对肿瘤诱导抑制的敏感性中的作用。

项目成果

Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression.

用非常低亲和力的肽配体启动可产生具有增强功能的 CD8( ) T 细胞效应器，但更容易受到转化生长因子 (TGF)β 介导的抑制。

• 发表时间: 2011-11
• 作者: O'Sullivan, Jeremy A;Zloza, Andrew;Kohlhapp, Frederick J;Moore, Tamson V;Lacek, Andrew T;Dulin, Nickolai O;Guevara
• 通讯作者: Guevara

Development of tumor-infiltrating CD8+ T cell memory precursor effector cells and antimelanoma memory responses are the result of vaccination and TGF-ýý blockade during the perioperative period of tumor resection.

肿瘤浸润性 CD8 T 细胞记忆前体效应细胞和抗黑色素瘤记忆反应的发展是肿瘤切除围手术期接种疫苗和 TGF-β 阻断的结果。

• 发表时间: 2011-03-15
• 作者: Bellavance, Emily C;Kohlhapp, Frederick J;Zloza, Andrew;O'Sullivan, Jeremy A;McCracken, James;Jagoda, Michael C;Lacek, Andrew T;Posner, Mitchell C;Guevara
• 通讯作者: Guevara