Activation of pDCs in Murine Tumor Models

小鼠肿瘤模型中 pDC 的激活

• 批准号: 8135419
• 负责人: WILLEM W OVERWIJK
• 金额: $ 27.37万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8135419
• 关键词: Agonist; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cells; Collaborations; Complex; Data; Dendritic Cells; Goals; Human; Immune response; Immune system; Immunotherapy; In Situ; In Vitro; Lead; Ligands; Mediating; Modeling; Molecular; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Play; Positioning Attribute; Role; Signal Transduction; T-Lymphocyte; TLR7 gene; Testing; Therapeutic Intervention; Toll-like receptors; Transgenic Organisms; Tumor Immunity; Vaccines; adaptive immunity; base; immune activation; improved; in vivo; melanoma; mouse model; pathogen; prevent; small molecule; tumor

Strong adaptive immunity depends on a strong innate immune response triggered by pathogen-derived molecules, such as Toll-Like Receptor (TLR) ligands. Current cancer vaccines typically induce tumor-specific T cells but no tumor regression. This may be because tumors are deficient in TLR ligands, reducing innate immune activation in tumors and thereby limiting the priming, accumulation, in situ activation and anti-tumor effector function of tumor-specific T cells. Plasmacytoid Dendritic Cells (pDCs) are cells of the innate immune system that critically orchestrate both innate and adaptive immune responses. pDCs have been found inside human tumors and are therefore potentially ideal targets for therapeutic intervention with TLR7 and TLR9 agonists which activate pDCs. However, it is unknown whether intratumoral pDCs are activated or whether they can respond to TLR agonist stimulation in vivo, and what the downstream effects of such activation are for innate and adaptive anti-tumor immunity. In addition, little is known about the mechanism through which pDCs could stimulate innate and adaptive anti-tumor immunity in vivo. Since immune responses are complex, they can only be fully understood through in vivo studies. We have developed a mouse model that allows us to study the presence and function of pDCs in tumors in vivo. We found that non-activated pDCs were present in murine melanoma. TLR agonist-activated pDCs could activate conventional mDCs, enhancing their capacity to prime tumor-specific T cells in vivo. Furthermore, activated pDCs potently activated NK cells in vivo to induce tumor destruction and de novo priming of additional tumorspecific CD8+ T cells. Building on the gplOO-specific TCR transgenic pmel-1 mouse model we have previously developed, we also found that in vivo activation of pDCs with TLR agonists enhanced tumor regression mediated by vaccine-induced, gplOO-specific CD8+ T cells. Based on these data we hypothesize that activation of intratumoral pDCs by TLR agonists in vivo will result in activation of mDCs and NK cells in the tumor leading to the induction of potent innate and adaptive anti-tumor immune responses. To test this hypothesis we will activate intratumoral pDCs in vivo with TLR agonists and test their ability to activate mDCs and NK cells and to induce the accumulation of tumor-specific T cells and tumor destruction, through the following Specific Aims: ¿ Specific Aim 1. Characterize the ability of intratumoral pDCs to interact with mDCs. ¿ Specific Aim 2. Evaluate the interactions between intratumoral pDCs and NK cells. ¿ Specific Aim 3. Determine whether intratumoral pDC activation by TLR agonists enhances T cellmediated anti-tumor function. Our goal is to identify principles which may be generalized towards improving immunotherapy of cancer patients.

强大的适应性免疫取决于病原体衍生的强大的先天免疫反应 分子，例如 Toll 样受体 (TLR) 配体。目前的癌症疫苗通常会诱导肿瘤特异性 T 细胞但肿瘤没有消退。这可能是因为肿瘤缺乏 TLR 配体，从而降低了先天性 肿瘤中的免疫激活，从而限制启动、积累、原位激活和抗肿瘤 肿瘤特异性 T 细胞的效应功能。浆细胞样树突状细胞 (pDC) 是先天性细胞 免疫系统关键地协调先天性和适应性免疫反应。 pDC 已 在人类肿瘤内部发现，因此是 TLR7 治疗干预的潜在理想靶标 和激活 pDC 的 TLR9 激动剂。然而，尚不清楚瘤内 pDC 是否被激活或 它们是否能够在体内对 TLR 激动剂刺激做出反应，以及这种下游效应是什么 激活用于先天性和适应性抗肿瘤免疫。此外，人们对其机制知之甚少 pDCs可以通过它刺激体内先天性和适应性抗肿瘤免疫。既然免疫了 反应很复杂，只有通过体内研究才能完全理解。我们开发了一个 小鼠模型使我们能够研究体内肿瘤中 pDC 的存在和功能。我们发现 小鼠黑色素瘤中存在未激活的 pDC。 TLR 激动剂激活的 pDC 可以激活 传统的 mDC，增强它们在体内启动肿瘤特异性 T 细胞的能力。此外，还激活了 pDC 在体内有效激活 NK 细胞，诱导肿瘤破坏并从头启动额外的肿瘤特异性 CD8+ T 细胞。基于 gp100 特异性 TCR 转基因 pmel-1 小鼠模型，我们有 先前开发的，我们还发现用 TLR 激动剂体内激活 pDC 增强肿瘤 由疫苗诱导的gp100特异性CD8+T细胞介导的消退。根据这些数据我们假设 体内 TLR 激动剂激活瘤内 pDC 将导致 mDC 和 NK 细胞的激活 肿瘤导致诱导有效的先天性和适应性抗肿瘤免疫反应。为了测试这个 假设我们将用 TLR 激动剂在体内激活瘤内 pDC，并测试它们的激活能力 mDC 和 NK 细胞，并通过诱导肿瘤特异性 T 细胞的积累和肿瘤破坏 具体目标如下： ¿ 具体目标 1. 表征瘤内 pDC 与 mDC 相互作用的能力。 ¿ 具体目标 2. 评估瘤内 pDC 和 NK 细胞之间的相互作用。 ¿ 具体目标 3. 确定 TLR 激动剂对瘤内 pDC 的激活是否增强 T 细胞介导的作用 抗肿瘤功能。 我们的目标是确定可推广用于改善癌症免疫治疗的原则 患者。