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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

批准号：
9379209
负责人：
Roza Insafetdinovna Nurieva
金额：
$ 8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9379209
关键词：
Biological Response Modifiers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Etiology Cause of Death Cell physiology Cells Clinical Data Development Future Gene Expression Microarray Analysis Growth Human Immune Immune Tolerance Immune response Immune system Immunosuppressive Agents Immunotherapy Implant In Vitro Incidence Laboratories Lead Lymphoma Malignant Neoplasms Melanoma Cell Methods Molecular Mus Neoplasm Metastasis Obstruction Outcome Patients Property Reagent Regulation Regulatory T-Lymphocyte Relapse Research Resistance Risk Factors Role Sampling Small-Cell Lymphoma System T-Lymphocyte Technology Testing Therapeutic Time Tumor Antigens Tumor Tissue Work base cancer immunotherapy cancer type cytotoxic cytotoxicity improved in vivo innovation insight knockout gene melanoma memory recall mouse model neoplastic cell novel novel therapeutic intervention pre-clinical prevent response screening tool tumor ubiquitin-protein ligase yeast two hybrid system

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