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.

总结 CD 4 + T细胞在抗肿瘤治疗策略的设计中是一个研究不足但重要的靶点 旨在重塑肿瘤微环境，增强抗肿瘤CTL的功能。近年 已经看到通过免疫疗法治疗黑色素瘤和其他癌症的实施。 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，但答复率 很低CD 4 + T细胞在控制肿瘤生长中也起着关键作用。肿瘤的生长在 缺乏CD 4 + T细胞，并且抗肿瘤CD 4 + T细胞应答的诱导可以显著增强肿瘤细胞的免疫应答。 肿瘤特异性CTL的功能和存活。因此，它们代表了一种未充分探索的替代方案 治疗靶点，关于它们对当前检查点阻断的反应知之甚少 免疫疗法我们的初步数据表明，在小鼠黑色素瘤模型中， CD 4 + T细胞的募集对抗原水平非常敏感。低水平的肿瘤抗原不能招募 即使是相对高亲和力的CD 4 + T细胞也能参与抗肿瘤反应，这表明一个关键的调节因子， 对肿瘤的辅助性T细胞反应是TCR亲和力和随后的T细胞募集。这些发现让我们 假设旨在降低CD 4 + T细胞的TCR活化阈值的策略将增强它们的免疫应答。 募集到响应中以及它们的抗肿瘤功能。我们将从两个方面来检验这个假设。一是 将测试低TCR亲和力的T辅助细胞是否被招募到抗黑素瘤反应中，以及 确定常规检查点阻断（抗PD-1和/或抗CTLA-4）对其募集的影响 和功能其次，我们将确定是否靶向Shp-1，一种调节活性的磷酸酶， 各种TCR近端信号级联，将诱导较低的CD 4 + T细胞活化阈值， 与检查点阻断相结合，改善其对黑色素瘤的反应并改善其效应子功能。在我们 之前发表的研究，我们已经开发出强大的工具，使我们能够分析CD 4 + T细胞 包括用于分析CD 4 + TCR库发育的模型系统 和进化，使用逆转录病毒表达载体产生TCR“逆转录”小鼠的方法， 常规TCR转基因小鼠，两者对相同抗原具有特异性但具有不同TCR亲合力。我们 我预计，这里提出的实验将为黑色素瘤的设计提供重要的基础。 针对T辅助细胞的免疫策略。