Recruitment of melanoma-specific CD4+ T cells

黑色素瘤特异性 CD4 T 细胞的募集

• 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
• 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

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细胞代表了抗肿瘤疗法策略设计的一个理解但重要的目标 旨在重新塑造肿瘤微环境并增强抗肿瘤CTL的功能。近年来 已经看到实施免疫疗法来治疗黑色素瘤和其他癌症 在体内激活和/或营救肿瘤特异性CTL。虽然承诺采用这些方法，但响应率 低。 CD4+ T细胞在控制肿瘤生长中也起着关键作用。肿瘤生长在 CD4+ T细胞的缺乏以及抗肿瘤CD4+ T细胞反应的诱导可以极大地增强 肿瘤特异性CTL的功能和存活。因此，它们代表了一个未充分置换的替代方案 治疗靶标，关于当前检查点封锁的响应，知之甚少 免疫疗法。我们的初步数据表明，在黑色素瘤的小鼠模型中，肿瘤特异性 CD4+ T细胞的募集对抗原水平敏感。低水平的肿瘤抗原无法募集 即使是相对较高的流行病CD4+ T细胞进入抗肿瘤反应，表明一个关键因素调节 T辅助对肿瘤的反应是TCR亲和力和随后的T细胞募集。这些发现带领我们 假设旨在降低CD4+ T细胞的TCR激活阈值的策略将增强其 招募响应及其抗肿瘤功能。我们将以两种方式检验这一假设。首先，我们 将测试较低的TCR亲和力T辅助细胞是否募集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）对其招聘的影响 和功能。其次，我们将确定SHP-1的靶向是调节活性的磷酸酶 在各种TCR近端信号级联反应中，将诱导较低的CD4+ T细胞激活阈值 对黑色素瘤的反应并改善其效应子功能，并结合检查点阻滞。在我们的 先前发表的研究，我们开发了强大的工具，可以使我们能够分析CD4+ T细胞 以克隆为基础的响应，包括用于分析CD4+ TCR曲目开发的模型系统 和进化，使用逆转录病毒表达载体和两种产生TCR“恢复”小鼠的方法 常规的TCR转基因小鼠，既适用于相同的抗原，但具有不同的TCR。我们 预计此处提出的实验将为设计黑色素瘤的设计提供重要的基础 靶向T辅助细胞的免疫治疗策略。