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

项目摘要 癌症免疫疗法已经彻底改变了恶性肿瘤的治疗，但这些治疗方法仍然面临 在许多患者中存在巨大的挑战和有限的疗效。为了克服这些局限性， 对于CD 8 T细胞靶向治疗，需要更多地了解其他免疫参与者，特别是 CD 4辅助T细胞，帮助抗肿瘤CD 8 T细胞免疫。CD 4 T细胞被认为促进CD 8 T细胞 通过CD 40依赖性“许可”抗原呈递细胞（APC）引发CD 8 T细胞的免疫应答。是 现在清楚的是，CD 8 T细胞几乎完全依赖于传统的1型树突状细胞（cDC 1）进行启动， 抗肿瘤和病毒抗原。然而，没有研究直接确定了启动CD 4 T细胞的APC 负责许可或明确识别cDC 1作为体内CD 4许可的靶点。拟议研究 阐明了引发抗肿瘤CD 4 T细胞和介导CD 4帮助肿瘤细胞增殖所需的细胞相互作用。 增强抗肿瘤CD 8 T细胞应答。最重要的假设是，在肿瘤来源的环境中， 抗原，cDC 1作为能够引发CD 4和CD 8 T细胞的自主平台发挥作用， 协调最佳抗肿瘤免疫所需的串扰。这将使用新的体内 基因模型允许选择性操纵cDC 1中的分子。本提案的目标1调查 cDC 1直接引发CD 4 T细胞对抗肿瘤衍生抗原的假设。这一目标将审查 免疫过程中抗原形式对体内CD 4 T细胞致敏的影响，然后比较抗肿瘤CD 4 T细胞 在模型中，MHC II类表达选择性失活或在cDC 1上诱导。目的2 研究了CD 4 T细胞间接为抗肿瘤CD 8 T细胞引发提供必要帮助的假设 和通过cDC 1上的CD 40信号传导的检查点阻断免疫疗法。这一目标将表征抗肿瘤 CD 8 T细胞应答和检查点阻断免疫疗法在荷瘤模型中的功效， 遗传上缺乏CD 4 T细胞的帮助。它还将定义CD 40依赖性帮助的直接细胞相互作用。在 从长远来看，拟议的工作将增加对癌症免疫相互作用的机械理解， 这可能有助于开发更广泛成功的免疫疗法和治疗。 此申请人是一个在一个机构的MD-PhD候选人，该机构长期以来一直支持医学科学家， 他们的培训的所有阶段，并正在与一个坚定的承诺辅导团队。拟议的培训计划 提供新的概念和技术培训，沿着科学、临床和职业发展活动 支持成为一名独立的物理学家，科学家，专注于发现 癌症免疫学，可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.