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

基本信息

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
项目类别：
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

项目摘要

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学。但是，有关压力如何影响肿瘤生长的详细信息和抗肿瘤免疫仍然缺失或了解不足。髓样衍生的补充剂细胞（MDSC）是越来越多地被认为是肿瘤免疫学的关键参与者，因为除了其基本角色在抑制效应子NK细胞，CD8+ T细胞和CD4+ T细胞中，它们在肿瘤生长中也起着直接的作用，分化和转移。确切的压力，尤其是肾上腺压力如何影响MDSC 未知。解决这一难题的是该应用程序的总体目标。这个假设建议是，慢性应激期间去甲肾上腺素水平的升高会激活β-肾上腺素受体（β- AR）在MDSC中的信号传导并增加了MDSC的促肿瘤功能和存活，均在原发性肿瘤中微环境和转移部位（肺和骨髓）。我们将以两个具体的目的解决这一假设：目标1：测试β2-AR信号传导的假设调节MDSC的分布，积累和功能在肿瘤中的目标2：确定 β2-AR信号传导改变MDSC在肿瘤中存活的机制。我们将使用转移4T1 和非转移性AT-3鼠乳腺癌模型。 4T1是一种临床相关的乳腺癌模型原始植入乳腺植入并转移至肺部以及其他部位，是已知会诱导MDSC积累。从原发性乳腺建立了AT-3肿瘤细胞系 MMTV-PYMT转基因小鼠模型的癌，并在诱导CD11b+ GR-1+ MDSC反应后植入。我们将使用三种不同的策略来减少和/或阻止肾上腺素信号传导。这些方法包括遗传（β2AR - / - 小鼠与窝窝型野生型对照相比），药物（β-AR 与PBS相比）和物理（冷住房与温暖的住房）。总共提议研究将提供重要的研究经验，该研究将揭示β2-肾上腺素信号在尤其是MDSC的肿瘤生长，尤其是MDSC的免疫抑制功能，并揭示了新的机制慢性应激促进肿瘤的生长。这项培训赠款将增强我体验许多其他关键职业建设机会的能力将大大增加获得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在免费领域学习新技术的机会，例如基因组应用，这将扩大我的专业知识和独立性。