Grail-targeting breaks the immune tolerance to melanoma

圣杯靶向打破了对黑色素瘤的免疫耐受

基本信息

项目摘要

Abstract Efficacy of anti-cancer immunotherapy is limited due to various tumor evasion mechanisms including the tolerance induction of tumor-reactive T cells. Therefore, strategies to break T cell tolerance and thereafter enhance T-cell cytotoxicity towards tumor cells are needed. One such innovative and rational approach is to manipulate the intrinsic properties of T cells by suppressing the activity of tolerance-associated factors. We have acknowledged the E3 ubiquitin ligase, Grail as an essential component of T-cell tolerance and showed that Grail deficiency resulted in CD4+ T cell hyper-responsiveness and defective regulatory T cell suppressive function. Thus, targeting Grail may help to break tumor immune tolerance; however, the role of Grail in tumor development and in the function of cytotoxic CD8+ T lymphocytes (CTLs) remains unknown. Our preliminary data show that loss of Grail enhanced cytolytic functionality of CTLs. Furthermore, utilizing lymphoma tumors, we have determined that Grail-deficient CTLs are essential for control of established tumor. Remarkably, Grail expression level was significantly higher in CTLs from lymphoma patients, suggesting the novel role of Grail in immune tolerance to lymphoma and providing a rationale for exploring the role of Grail in melanoma that is often observed in a lymphoma setting. Further understanding the function of Grail in different cancer types will be beneficial for development of common therapeutic approach for these malignancies. We have evidence that Grail deficiency in mice confers control of implanted B16 melanoma tumor. Moreover, in melanoma patient samples, we found high Grail expression in CD8+ T cells from the tumor tissues, suggesting that Grail expression in the immune cells could be a big obstruction for controlling melanoma as well. Therefore, we propose to investigate the therapeutic potential of Grail-targeted CTLs for melanoma as well as their regulatory mechanisms using both mouse and human systems. In Aim 1, we will investigate the role of Grail KO CTLs in melanoma growth control by utilizing gene knockout approaches. We will also assess the mechanism(s) whereby Grail controls anti-tumor function and persistence of CTLs. Moreover, we will try to identify targets through which Grail facilitates control of tumor-reactive CD8+ T cell function by employing cutting edge technologies, including two-hybrid screening and microarray analysis of gene expression. In Aim 2, we will establish an efficient Grail targeting approach for human and mouse CD8+ T cells in order to improve the efficiency of adoptive therapy for established malignancies. Overall the proposed research will help to validate Grail as a functional mediator of immune tolerance in melanoma as well as evaluate the therapeutic potential of Grail deficient CD8+ T cells for melanoma treatment. The implications from this work are significant since the results will provide mechanistic insights into the understanding of the function of Grail in melanoma and will potentially lead to the development of novel targeted treatments to reverse immune tolerance in melanoma and other malignancies.
摘要

项目成果

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Roza Insafetdinovna Nurieva其他文献

Roza Insafetdinovna Nurieva的其他文献

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{{ truncateString('Roza Insafetdinovna Nurieva', 18)}}的其他基金

Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors
检查点抑制剂引起的免疫相关毒性的基于机制的治疗策略
  • 批准号:
    10753628
  • 财政年份:
    2023
  • 资助金额:
    $ 8万
  • 项目类别:
Role of E3 Ubiquitin ligase RNF133 in T cell function and tolerance
E3 泛素连接酶 RNF133 在 T 细胞功能和耐受性中的作用
  • 批准号:
    10311074
  • 财政年份:
    2019
  • 资助金额:
    $ 8万
  • 项目类别:
Role of Cul4A in Governing Th2-Type Tolerance
Cul4A 在控制 Th2 型耐受中的作用
  • 批准号:
    10198025
  • 财政年份:
    2018
  • 资助金额:
    $ 8万
  • 项目类别:
Role of Cul4A in Governing Th2-Type Tolerance
Cul4A 在控制 Th2 型耐受中的作用
  • 批准号:
    9770641
  • 财政年份:
    2018
  • 资助金额:
    $ 8万
  • 项目类别:
STAT1: New regulator of inflammatory Th17 and Th2 cells
STAT1:炎症 Th17 和 Th2 细胞的新调节因子
  • 批准号:
    9112386
  • 财政年份:
    2016
  • 资助金额:
    $ 8万
  • 项目类别:
STAT1: New regulator of inflammatory Th17 and Th2 cells
STAT1:炎症 Th17 和 Th2 细胞的新调节因子
  • 批准号:
    9206467
  • 财政年份:
    2016
  • 资助金额:
    $ 8万
  • 项目类别:
Role of Grail in maintaining humoral immune tolerance
Grail 在维持体液免疫耐受中的作用
  • 批准号:
    9089880
  • 财政年份:
    2015
  • 资助金额:
    $ 8万
  • 项目类别:
Regulation of T cell activation and tolerance by Grail
Grail 对 T 细胞活化和耐受的调节
  • 批准号:
    8468985
  • 财政年份:
    2009
  • 资助金额:
    $ 8万
  • 项目类别:
Regulation of T cell activation and tolerance by Grail
Grail 对 T 细胞活化和耐受的调节
  • 批准号:
    7869435
  • 财政年份:
    2009
  • 资助金额:
    $ 8万
  • 项目类别:
Regulation of T cell activation and tolerance by Grail
Grail 对 T 细胞活化和耐受的调节
  • 批准号:
    7700519
  • 财政年份:
    2009
  • 资助金额:
    $ 8万
  • 项目类别:
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