Overcoming stress driven suppression of the anti-tumor immune response in cancer - understanding the MDSC piece of the puzzle

摘要：慢性压力会抑制免疫力。然而，关于应激如何影响肿瘤生长的细节 而抗肿瘤免疫仍然缺乏或知之甚少。髓系来源的抑制细胞(MDSCs)是 越来越被认为是肿瘤免疫学中的关键参与者，因为除了它们的基本作用外， 在抑制效应NK细胞、CD8+T细胞和CD4+T细胞方面，它们也在肿瘤生长中发挥直接作用， 分化和转移。压力，特别是肾上腺素能应激，究竟是如何影响MDSCs的，在很大程度上 未知。解决这一难题是本应用程序的总体目标。这是一个假设 有观点认为，慢性应激时去甲肾上腺素水平升高会激活β肾上腺素能受体(β-AR)。 AR)信号在MDSCs中传递，并增加MDSCs的亲肿瘤功能和生存时间，两者都存在于原发肿瘤中 在微环境和转移部位(肺和骨髓)。 我们将在两个具体目标中解决这一假设：目标1：测试β2-AR信号转导的假设 调节MDSC在肿瘤中的分布、蓄积和功能及目标2：确定 β2-AR信号改变肿瘤中多药耐药干细胞存活的机制。我们将使用转移性4T1 和非转移性AT-3小鼠乳腺癌模型。4T1是一种临床相关的乳腺癌模型 原位种植于乳腺并转移至肺及其他部位 已知会导致MDSC积聚。从原代乳腺建立AT-3肿瘤细胞系 MMTV-PYMT转基因小鼠模型的建立及诱导CD11b+Gr-1+MDSC应答的研究 植入。我们将使用三种不同的策略来减少和/或阻断肾上腺素能信号。这些 方法包括遗传(β2AR-/-小鼠与野生型对照相比)、药物(β-AR 阻滞剂(与PBS相比)和生理(冷房与温房)。总之，我的建议是 研究将提供重要的研究经验，揭示β2-肾上腺素能信号在 肿瘤生长，特别是MDSCs的免疫抑制功能，并揭示了新的机制 慢性压力通过这种方式促进肿瘤生长。 这笔培训补助金将增强我体验许多其他关键的职业发展机会的能力，这些机会包括 将大大增加我获得K99/R00奖和我自己在 未来。它还可以帮助我利用机会在免费的领域学习新技术， 例如基因组应用，这将扩大我的专业知识和独立性。

SUMMARY: Chronic stress can suppress immunity. However, details about how stress affects tumor growth and anti-tumor immunity are still missing or poorly understood. Myeloid derived suppresser cells (MDSCs) are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Exactly how stress, particularly adrenergic stress, affects MDSCs is largely unknown. Addressing this piece of the puzzle is the overall goal of this application. The hypothesis of this proposal is that increased level of norepinephrine during chronic stress activates β- adrenergic receptor (β- AR) signaling in MDSCs and increases pro-tumor functions and survival of MDSCs, both in the primary tumor microenvironment and in metastatic sites (lung and bone marrow). We will address this hypothesis in two specific aims: Aim 1: To test the hypothesis that β2-AR signaling regulates MDSC distribution, accumulation and function in tumors and Aim 2: To determine mechanisms by which β2-AR signaling alters MDSC survival in the tumor. We will use metastatic 4T1 and non-metastatic AT-3 murine breast cancer models. 4T1 is a clinically relevant model of breast cancer that is implanted orthotopically in the mammary gland and metastasizes to the lung, as well as other sites and is known to induce MDSC accumulation. AT-3 tumor cell line was established from a primary mammary gland carcinoma of an MMTV-PyMT transgenic mouse model and induces CD11b+Gr-1+ MDSC response after implantation. We will use three different strategies to reduce and/or block adrenergic signaling. These approaches include genetic (β2AR-/- mice compared to littermate wild-type controls), pharmaceutical (beta-AR blockers compared to PBS) and physiological (cold housing versus warm housing). Altogether, my proposed research will provide an important research experience that will reveal the key role of β2-adrenrgic signaling in tumor growth in general, and immune-inhibitory functions of MDSCs in particular, and reveal new mechanisms by which chronic stress promotes tumor growth. This Training Grant will enhance my ability to experience many other critical career-building opportunities that will greatly increase my chances of obtaining a K99/R00 award and my own independent laboratory in the future. It can also help me to take advantage of opportunities to learn new techniques in complimentary fields, such as genomic applications, which will expand my expertise and independence.