Neuro-Immune Interaction in Cancer Development

虽然实体肿瘤中神经的存在已经观察了几百年，但对 这些神经对肿瘤生长的影响只是在最近10年才开始的。这项工作的大部分都有 主要集中在神经递质对肿瘤细胞生长和转移的影响，而免疫细胞也 表达多种神经递质的受体，具有免疫激活和免疫抑制作用 属性。在使用小鼠乳腺癌模型的初步研究中，我们发现 感觉神经的存在是适应性免疫系统抑制肿瘤所必需的。此外， 阻断感觉神经产生的一种特殊神经递质--降钙素基因相关肽 抑制肿瘤生长和改善T细胞对肿瘤的渗透，表明既支持肿瘤又反对肿瘤 乳腺癌患者的感觉神经活动。在这个项目中，我们将破译感觉神经是如何促进 对肿瘤的适应性免疫反应。我们还将研究CGRP抑制的机制 改善肿瘤控制，以及这种治疗是否能与抗PD-1免疫治疗协同作用。最后，我们 将评估是否存在感觉神经、肾上腺素能神经或特定的神经递质，包括 降钙素基因相关肽与乳腺癌患者的免疫浸润和化疗反应有关。总括 这些研究将提供一种潜在的新的免疫治疗途径的关键信息，这种途径可以 在患者中进行调节，以促进肿瘤控制。

While the presence of nerves in solid tumors has been observed for hundreds of years, investigation of the impact of these nerves on tumor growth has only been initiated in the last 10 years. The bulk of this work has focused on the impact of neurotransmitters on tumor cell growth and metastasis, however immune cells also express receptors for a wide variety of neurotransmitters, which can have immune-activating and immuneinhibiting properties. In preliminary studies using a murine breast cancer model, we have found that the presence of sensory nerves is necessary for tumor inhibition by the adaptive immune system. Furthermore, blockade of a specific neurotransmitter produced by sensory nerves, calcitonin gene related peptide (CGRP) inhibited tumor growth and improved T cell infiltration into tumors, suggesting both pro- and anti-tumor activities for sensory nerves in breast cancer. In this project, we will decipher how sensory nerves promote adaptive immune responses to tumors. We will also investigate the mechanism by which CGRP inhibition improves tumor control, and whether this treatment can synergize with anti-PD-1 immunotherapy. Finally, we will evaluate whether presence of sensory nerves, adrenergic nerves, or specific neurotransmitters including CGRP correlate with immune infiltration and response to chemotherapy in breast cancer patients. Overall these studies will provide critical information on a potentially novel immunotherapeutic pathway that can be modulated in patients to promote tumor control.