The Role of Schwann Cells in the Progression of Melanoma

项目摘要 临床和实验证据表明，癌症的进展取决于以下因素的相互作用 恶性细胞与其他成分的肿瘤微环境(TME)。癌症相关基因的功能 成纤维细胞、内皮细胞、肿瘤浸润性免疫细胞等基质因子对肿瘤的调控作用 对生长和进展进行了深入的研究。外周神经元现在也被认为是 肿瘤环境的重要组成部分。肿瘤的神经支配程度与癌症直接相关。 进展和转移，与患者的生存呈负相关。几个负责的机制 神经介导的癌症进展已被提出，包括调节神经递质的活性 以及神经肽对肿瘤相关血管和免疫浸润的影响。到目前为止，这一领域的工作主要是 重点是自主神经系统在促进癌症中的作用，几份报告也涉及 躯体传入神经。然而，周围神经系统的神经胶质细胞在 促进癌症进展仍不清楚。具体地说，排除神经侵袭的过程， 雪旺细胞(SCs)是周围神经系统的主要神经胶质细胞，在多大程度上调节TME和 促进癌症进展还没有被研究过。我们证明了干细胞存在于人类体内 黑色素瘤组织，并在几个黑色素瘤小鼠模型中加速肿瘤生长和转移。 我们发现，这种作用是由于修复干细胞的激活和它们对第三级淋巴的抑制 结构(TLS)的形成和保护性抗肿瘤免疫反应。然而，供应链的机制 TME的免疫调节作用尚不清楚。我们假设黑色素瘤相关修复干细胞 促进对黑色素瘤的免疫耐受，靶向是一种新的针对黑色素瘤的免疫治疗方法 癌症。为了验证我们的假设，我们将追求两个具体目标：1)确定 修复干细胞在黑色素瘤中的免疫调节，以及2)靶向修复干细胞在黑色素瘤中作为一种新的方法 去接受治疗。在目标1中，我们将研究干细胞如何促进癌症的免疫耐受并阻碍TLS 肿瘤的形成，重点是Slit2，MAG和p75NTR信号机制。转基因 免疫活性的自体BrafCA黑色素瘤和慢Weller变性WldS小鼠模型 将会被利用。在目标2中，我们将测试靶向黑色素瘤相关修复干细胞是否破坏免疫 耐受性与目前的抗PD-1和抗CTLA4疗法协同作用。该提案的主要影响 将机制验证依赖于SC来维持免疫耐受--这是一大挑战 在目前晚期恶性肿瘤的治疗中。我们希望我们的研究结果能验证一部小说 以肿瘤相关胶质细胞为靶点的黑色素瘤免疫治疗方法 可能也适用于其他类型的癌症。

Project Summary Clinical and experimental evidence demonstrate that cancer progression depends on the interactions of malignant cells with other elements of the tumor microenvironment (TME). Functions of cancer-associated fibroblasts, endothelial cells, tumor-infiltrating immune cells and other stromal elements in regulating tumor growth and progression have been intensively investigated. Peripheral neurons are now also recognized as important constituents of the tumor milieu. The degree of tumor innervation is directly correlated with cancer progression and metastasis, and inversely correlated with patient survival. Several mechanisms responsible for nerve-mediated cancer progression have been proposed, including regulatory activity of neurotransmitters and neuropeptides on tumor-associated vasculature and immune infiltrate. Thus far, work in this area largely focused on the role of the autonomic nervous system in promoting cancer, with several reports also implicating the somatic afferent innervation. However, the role of the neuroglia of the peripheral nervous system in promoting cancer progression remains unclear. Specifically, excluding the process of perineural invasion, the extent to which Schwann cells (SCs), principal glia of the peripheral nervous system, modulate TME and facilitate cancer progression has not been investigated. We demonstrated that SCs are present in human melanoma tissue, and that they accelerate tumor growth and metastasis in several melanoma mouse models. We discovered that this effect is due to the activation of repair SCs, and their inhibition of tertiary lymphoid structure (TLS) formation and protective anti-tumor immune responses. However, the mechanism of SC immunomodulation in TME remains unknown. We hypothesize that melanoma-associated repair SCs promote immune tolerance to melanoma, and their targeting is a novel immunotherapy approach against cancer. To test our hypothesis, we will pursue two Specific Aims: 1) determine the mechanism of immunomodulation by repair SCs in melanoma, and 2) target repair SCs in melanoma as a novel approach to therapy. In Aim 1, we will examine how SCs promote immune tolerance of cancer and impede TLS formation in tumors, focusing on Slit2, MAG, and p75NTR signaling mechanisms. Transgenic immunocompetent autochthonous BrafCA melanoma and slow Wallerian degeneration WldS mouse models will be utilized. In Aim 2, we will test whether targeting melanoma-associated repair SCs to break immune tolerance synergizes with current anti-PD-1 and anti-CTLA4 therapies. The primary impact of the proposal will be mechanistic verification of SC-dependent maintenance of the immune tolerance – a major challenge in the current treatment of advanced malignancies. We expect that our results will validate a novel immunotherapy approach for melanoma based on targeting tumor-associated glia – an approach which will likely be applicable to other types of cancer.