Activation of pDCs in Murine Tumor Models

小鼠肿瘤模型中 pDC 的激活

• 批准号: 8332330
• 负责人: WILLEM W OVERWIJK
• 金额: $ 26.36万
• 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/8332330
• 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.

强的适应性免疫依赖于病原体来源的免疫原性物质引发的强的先天免疫应答。 分子，如Toll样受体（TLR）配体。目前的癌症疫苗通常诱导肿瘤特异性 T细胞，但没有肿瘤消退。这可能是因为肿瘤缺乏TLR配体，减少了先天性 肿瘤中的免疫激活，从而限制引发、积累、原位激活和抗肿瘤 肿瘤特异性T细胞的效应子功能。浆细胞样树突状细胞（pDC）是先天性巨噬细胞的细胞。 关键性地协调先天性和适应性免疫应答免疫系统。pDC已经被 在人类肿瘤中发现，因此是TLR 7治疗干预的潜在理想靶点 和激活pDC的TLR 9激动剂。然而，尚不清楚肿瘤内pDC是否被激活或 它们是否能在体内对TLR激动剂刺激产生应答，以及这种应答的下游效应是什么， 激活是用于先天性和适应性抗肿瘤免疫。此外，对该机制知之甚少 pDC可以通过该途径在体内刺激先天性和适应性抗肿瘤免疫。由于免疫 反应是复杂的，它们只能通过体内研究才能完全理解。我们已经开发出一种 小鼠模型，使我们能够在体内研究肿瘤中pDC的存在和功能。我们发现 未活化的pDC存在于鼠黑素瘤中。TLR激动剂激活的pDC可以激活 常规mDC，增强其在体内引发肿瘤特异性T细胞的能力。此外，激活 pDC在体内有效地激活NK细胞以诱导肿瘤破坏和额外的肿瘤特异性抗原的从头引发。 CD 8 + T细胞。基于gp 100特异性TCR转基因pmel-1小鼠模型， 我们还发现，用TLR激动剂体内活化pDC可增强肿瘤细胞的增殖， 通过疫苗诱导的gp 100特异性CD 8 + T细胞介导的消退。根据这些数据，我们假设 TLR激动剂在体内对肿瘤内pDC的激活将导致肿瘤内mDC和NK细胞的激活， 该肿瘤导致诱导有效的先天性和适应性抗肿瘤免疫应答。为了验证这一 假设我们将用TLR激动剂在体内激活肿瘤内pDC，并测试它们激活肿瘤内pDC的能力。 mDCs和NK细胞，并诱导肿瘤特异性T细胞的积累和肿瘤破坏，通过 以下具体目标： 具体目标1.表征肿瘤内pDC与mDC相互作用的能力。 具体目标2.评估肿瘤内pDC和NK细胞之间的相互作用。 具体目标3.确定通过TLR激动剂的肿瘤内pDC活化是否增强T细胞介导的免疫应答。 抗肿瘤作用 我们的目标是确定原则，可能会推广到改善免疫疗法的癌症 患者