The role of type 1 dendritic cells in CD4 and CD8 T cell anti-tumor immunity

项目总结 癌症免疫疗法已经给恶性肿瘤的治疗带来了革命性的变化，但这些疗法仍然面临 许多患者面临巨大的挑战和有限的疗效。为了克服这些限制，改进了战略 对于CD8 T细胞靶向治疗，将需要更多地了解其他免疫参与者，特别是 CD4辅助T细胞，有助于抗肿瘤CD8 T细胞免疫。CD4T细胞被认为促进CD8T细胞 激活CD8T细胞的抗原提呈细胞(APC)依赖于CD40的“许可”反应。它是 现在清楚的是，CD8T细胞几乎完全依赖于传统的1型树突状细胞(CDc1)来启动 抗肿瘤和病毒抗原。然而，还没有研究直接确定启动CD4T细胞的APC 在体内负责许可或明确将cDC1确定为CD4许可的目标。拟议的研究 阐明了启动抗肿瘤的CD4T细胞所需的细胞相互作用和介导CD4Help 增强抗肿瘤CD8 T细胞反应。最重要的假设是，在肿瘤来源的背景下 抗原，cDC1作为一个自主平台，能够同时启动CD4和CD8 T细胞和 协调它们的串扰，以获得最佳的抗肿瘤免疫。这将用新颖的活体实验进行测试。 允许选择性操控cdc1中分子的遗传模型。本提案的目标1调查 CDC1直接启动CD4T细胞对抗肿瘤抗原的假说。这一目标将审查 免疫过程中抗原形式对体内CD4T细胞活化的影响及抗肿瘤作用的比较 在cDC1上选择性失活或诱导MHC II类表达的模型中的细胞反应。目标2 探讨CD4T细胞间接为抗肿瘤CD8T细胞启动提供必要帮助的假说 而检查点通过CD40信号阻断免疫治疗。这一目标将成为抗肿瘤的特征 CD8T细胞反应和检查点阻断免疫治疗在荷瘤模型中的疗效 遗传性缺乏CD4T细胞的帮助。它还将定义CD40依赖的帮助的直接细胞相互作用。在 从长远来看，这项拟议的工作将增加对抗癌免疫相互作用的机制理解， 这可能有助于开发更广泛成功的免疫疗法和治疗方法。 此申请者是医学博士研究生，就读于一所长期支持内科科学家的机构。 所有阶段的培训，并正在与一个坚定的指导团队合作。拟议的培训计划 提供新的概念和技术培训，以及科学、临床和职业发展活动 支持成为一名独立的内科医生兼科学家的轨迹，专注于发现 癌症免疫学，可应用于开发新的治疗策略。

PROJECT SUMMARY Cancer immunotherapies have revolutionized the treatment of malignancies, but these therapeutics still face enormous challenges and limited efficacy in many patients. To overcome these limitations, improved strategies for CD8 T cell-targeted therapies will require increased understanding of how other immune players, particularly CD4 helper T cells, help in anti-tumor CD8 T cell immunity. CD4 T cells are thought to promote CD8 T cell responses by CD40-dependent “licensing” of the antigen presenting cells (APCs) that prime CD8 T cells. It is now clear that CD8 T cells rely almost exclusively on conventional type 1 dendritic cells (cDC1) for priming against tumor and viral antigens. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified cDC1 as the target of CD4 licensing in vivo. The proposed research elucidates the cellular interactions required for priming anti-tumor CD4 T cells and mediating CD4 help for augmenting anti-tumor CD8 T cell responses. The overarching hypothesis is that in the setting of tumor-derived antigens, cDC1 function as an autonomous platform capable of priming both CD4 and CD8 T cells and orchestrating their crosstalk required for optimal anti-tumor immunity. This will be tested using novel in vivo genetic models that allow for selective manipulation of molecules in cDC1. Aim 1 of this proposal investigates the hypothesis that cDC1 directly prime CD4 T cells against tumor-derived antigens. This aim will examine the effect of antigen form during immunization on CD4 T cell priming in vivo and then compare anti-tumor CD4 T cells responses in models where MHC class II expression is selectively inactivated or induced on cDC1. Aim 2 investigates the hypothesis that CD4 T cells indirectly provide necessary help for anti-tumor CD8 T cell priming and checkpoint blockade immunotherapy through CD40 signaling on cDC1. This aim will characterize anti-tumor CD8 T cell responses and efficacy of checkpoint blockade immunotherapy in tumor-bearing models that genetically lack CD4 T cell help. It will also define the direct cellular interactions for CD40-dependent help. In the long term, the proposed work will increase mechanistic understanding of immune interactions against cancers, which may aid the development of more widely successful immunotherapies and treatments. This applicant is an MD-PhD candidate at an institution with a long history of supporting physician-scientists at all stages of their training and is working with a strongly committed mentoring team. The proposed training plan provides new conceptual and technical training, along with scientific, clinical, and career development activities that support a trajectory to become an independent physician-scientist focused on discovering mechanisms of cancer immunology that may be applied to develop novel strategies for therapies.