Recruitment of melanoma-specific CD4+ T cells

黑色素瘤特异性 CD4 T 细胞的募集

基本信息

批准号：
9304062
负责人：
Matthew A Williams
金额：
$ 16.48万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304062
关键词：
Acute Adoptive Transfer Antigen-Presenting Cells Antigens Antiviral Response Avidity Bacterial Infections Binding Biological Models CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Clone Cells Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Dose Engineering Evolution Foundations Goals Helper-Inducer T-Lymphocyte Immune response Immune system Immunotherapeutic agent Immunotherapy Impairment In Vitro Inflammatory Lead MHC Class II Genes Malignant Neoplasms Mediating Methods Mus Oncolytic viruses Pathway interactions Phosphoric Monoester Hydrolases Play Population Publishing Recruitment Activity Regulatory T-Lymphocyte Role Shapes Signal Transduction Systems Analysis T-Cell Activation T-Lymphocyte TCR Activation Testing Therapeutic Transgenic Mice Tumor Antigens Tumor Immunity Virus Diseases Work base cancer type chimeric antigen receptor combat cytokine cytotoxicity design experimental study expression vector immune checkpoint blockade improved in vivo inhibitor/antagonist innovation macrophage melanoma mouse model outcome forecast prevent response success therapeutic target tool tumor tumor growth tumor microenvironment tumor specificity

项目摘要

Summary CD4+ T cells represent an understudied yet important target in the design of anti-tumor therapeutic strategies aimed at re-shaping the tumor microenvironment and enhancing the function of anti-tumor CTL. Recent years have seen the implementation of immunotherapies for the treatment of melanoma and other cancers via the activation and/or rescue of tumor-specific CTLs in vivo. While these approaches are promising, response rates are low. CD4+ T cells also play a critical role in the control of tumor growth. Tumor growth is accelerated in the absence of CD4+ T cells, and the induction of anti-tumor CD4+ T cell responses can dramatically enhance the function and survival of tumor-specific CTL. Therefore, they represent an underexplored alternative therapeutic target, and little is known regarding their response to current checkpoint blockade immunotherapies. Our preliminary data indicate that in a mouse model of melanoma, tumor-specific recruitment of CD4+ T cells is acutely sensitive to the level of antigen. Low levels of tumor antigen fail to recruit even relatively high avidity CD4+ T cells into the anti-tumor response, indicating that one key factor regulating the T helper response to tumors is TCR avidity and subsequent T cell recruitment. These findings have led us to hypothesize that strategies aimed at lowering TCR activation threshold of CD4+ T cells will enhance their recruitment into the response and their anti-tumor function. We will test this hypothesis in two ways. First, we will test whether low TCR avidity T helper cells are recruited into the anti-melanoma response, as well as determine the impact of conventional checkpoint blockade (anti-PD-1 and/or anti-CTLA-4) on their recruitment and function. Second, we will determine whether targeting of Shp-1, a phosphatase that regulates the activity of a variety of TCR proximal signaling cascades, will induce lower CD4+ T cell activation thresholds in response to melanoma and improve their effector function in combination with checkpoint blockade. In our previously published studies, we have developed powerful tools that will allow us to analyze the CD4+ T cell response on a clone-by-clone basis, including a model system for analyzing CD4+ TCR repertoire development and evolution, methods for generating TCR “retrogenic” mice using retroviral expression vectors and the two conventional TCR transgenic mice, both specific for the same antigen but with different TCR avidity. We anticipate that experiments proposed here will provide an important foundation for the design of melanoma immunotherapeutic strategies that target T helper cells.

概括 CD4+ T 细胞是抗肿瘤治疗策略设计中尚未得到充分研究的重要靶点近年来致力于重塑肿瘤微环境，增强抗肿瘤CTL功能。已经看到通过免疫疗法治疗黑色素瘤和其他癌症体内肿瘤特异性 CTL 的激活和/或拯救虽然这些方法很有希望，但反应率较高。 CD4+ T 细胞在控制肿瘤生长加速方面也发挥着关键作用。 CD4+ T 细胞的缺失，以及抗肿瘤 CD4+ T 细胞反应的诱导可以显着增强因此，它们代表了一种尚未充分探索的替代方案。治疗目标，但对其对当前检查点封锁的反应知之甚少我们的初步数据表明，在黑色素瘤小鼠模型中，肿瘤特异性 CD4+ T 细胞的募集对抗原水平非常敏感，低水平的肿瘤抗原无法募集。甚至相对高亲合力的 CD4+ T 细胞也能进入抗肿瘤反应，这表明调节的一个关键因素 T 辅助细胞对肿瘤的反应是 TCR 亲合力和随后的 T 细胞募集。这些发现引导我们。认为旨在降低 CD4+ T 细胞 TCR 激活阈值的策略将增强其我们将通过两种方式检验这一假设。将测试低 TCR 亲和力 T 辅助细胞是否被招募到抗黑色素瘤反应中，以及确定常规检查点封锁（抗 PD-1 和/或抗 CTLA-4）对其招募的影响其次，我们将确定是否靶向Shp-1（一种调节活性的磷酸酶）。多种 TCR 近端信号级联反应，将诱导较低的 CD4+ T 细胞激活阈值在我们的研究中，结合检查点封锁来应对黑色素瘤并改善其效应器功能。在之前发表的研究中，我们开发了强大的工具，使我们能够分析 CD4+ T 细胞基于克隆的响应，包括用于分析 CD4+ TCR 库开发的模型系统和进化，使用逆转录病毒表达载体生成TCR“逆转录”小鼠的方法以及这两种方法传统的 TCR 转基因小鼠，均对相同抗原具有特异性，但具有不同的 TCR 亲和力。预计这里提出的实验将为黑色素瘤的设计提供重要基础针对 T 辅助细胞的免疫治疗策略。