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

克服癌症中压力驱动的抗肿瘤免疫反应抑制——了解 MDSC 的难题

• 批准号: 10065427
• 负责人: Hemn Mohammadpour
• 金额: $ 1.22万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065427
• 关键词: 4T1; Address; Adoptive Transfer; Affect; Agonist; Apoptosis; Apoptotic; Award; BCL1 Oncogene; BCL2 gene; Behavior; Bioinformatics; Biology; Bone Marrow; Breast Cancer Model; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD95 Antigens; Cancer Biology; Carcinoma; Catecholamines; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Chronic stress; Clinical; Clinical Data; Data; Drug usage; Ethics; Exhibits; Future; Gene Expression; Generations; Genes; Genetic; Genomics; Goals; Grant; Homeostasis; Housing; ITGAM gene; Immune; Immune response; Immunity; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Implant; In Vitro; Induction of Apoptosis; Isoproterenol; Laboratories; Learning; Lung; Malignant Neoplasms; Mammary gland; Mediating; Mentors; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; Nerve; Nonmetastatic; Norepinephrine; Pathway interactions; Patients; Pharmacologic Substance; Pharmacology; Phosphorylation; Physiological; Play; Primary Neoplasm; Receptor Activation; Receptor Signaling; Recombinants; Research; Research Personnel; Resistance; Role; Running; STAT3 gene; Signal Transduction; Site; Spleen; Stress; System; T-Lymphocyte; TIE gene; Techniques; Testing; Tissues; Training; Transgenic Mice; Translating; Tumor Cell Line; Tumor Immunity; Tumor Tissue; Work; Writing; adrenergic block; adrenergic stress; anti-tumor immune response; beta-2 Adrenergic Receptors; beta-adrenergic receptor; cancer diagnosis; cancer therapy; career; clinically relevant; clinically significant; experience; genetic approach; implantation; improved outcome; in vivo; macrophage; mouse model; neoplastic cell; novel; pre-clinical; response; skills; training opportunity; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression; tumorigenic

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.

摘要：慢性压力可以抑制免疫力。然而，关于压力如何影响肿瘤生长的细节 和抗肿瘤免疫仍然缺失或知之甚少。髓源性抑制细胞（MDSC）是 越来越多地被认为是肿瘤免疫学的关键参与者，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细胞中，它们还在肿瘤生长中发挥直接作用， 分化和转移。确切地说，压力，特别是肾上腺素能压力，在很大程度上影响MDSC。 未知解决这个难题是这个应用程序的总体目标。这个假设 一种观点认为，慢性应激时去甲肾上腺素水平的升高激活了β-肾上腺素能受体（β- AR）信号传导，并增加MDSC的促肿瘤功能和存活，两者都在原发性肿瘤中。 微环境和转移部位（肺和骨髓）。 我们将在两个具体的目标来解决这个假设：目标1：为了验证假设，β 2-AR信号转导 调节MDSC在肿瘤中的分布、积聚和功能，目的2：确定 β 2-AR信号传导改变MDSC在肿瘤中存活的机制。我们将使用转移性4T1 和非转移性AT-3鼠乳腺癌模型。4T1是乳腺癌的临床相关模型， 原位植入乳腺并转移到肺以及其他部位， 已知可诱导MDSC蓄积。AT-3肿瘤细胞系是从原发性乳腺建立的 在MMTV-PyMT转基因小鼠模型的肿瘤中诱导CD11b + Gr-1 + MDSC应答， 置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（β 2 AR-/-小鼠与同窝野生型对照相比）、药物（β-AR 阻断剂与PBS相比）和生理学（冷室与温室）。总之，我的提议 这项研究将提供一个重要的研究经验，揭示β 2-肾上腺素能信号在 一般肿瘤生长，特别是MDSC的免疫抑制功能，并揭示新机制 慢性压力会促进肿瘤生长 这项培训补助金将提高我的能力，使我能够体验许多其他重要的职业发展机会， 这将大大增加我获得K99/R00奖和我自己的独立实验室的机会。 未来它还可以帮助我利用机会学习互补领域的新技术， 比如基因组应用，这将扩大我的专业知识和独立性。