Sexual dimorphism and the immuno-modulatory role of estrogen signaling in HNSCC

HNSCC 中雌激素信号的性别二态性和免疫调节作用

基本信息

批准号：
10751465
负责人：
SANA KARAM
金额：
$ 64.63万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-03 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751465
关键词：
Adhesions Affect Agonist Antigen Presentation Antigen Presentation Pathway Antigens Autoimmunity Automobile Driving Biological Biological Assay Biological Markers Blood Bone Marrow Castration Cell Cycle Kinetics Cell Differentiation process Cell Line Cell Survival Cell physiology Cells Cellular biology Chimera organism Circulation Clinical Trials Coculture Techniques Data Dendritic Cells Dependence Disease Dose Endosomes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens FLT3 ligand Female Flow Cytometry Fluorescent Antibody Technique Genetic Genetically Engineered Mouse Goals Gonadal Steroid Hormones Head and Neck Cancer High Endothelial Venule Homing Hormones Human Immune Immune response Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Incidence Inflammation Knockout Mice Label Lymphocyte Macrophage Male Castration Mediating Mediator Menopausal Status Migration Assay Modeling Molecular Mus Nodal Outcome Ovalbumin Ovariectomy Patients Phenotype Play Population Postmenopause Premenopause Process Proteomics Receptor Signaling Regulatory T-Lymphocyte Reporting Research Risk Role Selection for Treatments Sex Preselection Signal Transduction Site System T cell differentiation T-Cell Activation T-Lymphocyte Target Populations Testing Testosterone Therapeutic Time Toll-like receptors Tomatoes Tumor Antigens Up-Regulation Woman antagonist antigen-specific T cells cancer cell cancer therapy cellular targeting density draining lymph node effector T cell experimental study head and neck cancer patient immunoregulation improved in vitro Assay in vivo lymphatic vessel male men menopausal hormone therapy mouse model negative affect novel marker novel therapeutics pharmacologic pre-clinical programmed cell death protein 1 receptor response restraint sex sexual dimorphism therapy resistant trafficking treatment response tumor tumor microenvironment tumor progression uptake

项目摘要

ABSTRACT Head and neck cancer (HNSCC) afflicts mostly men. Female patients who develop HNSCC tend to be postmenopausal, with menopausal hormone therapy lowering their risk of developing the disease. We show that premenopausal female HNSCC patients have an improved response to therapy including immunotherapy (IO). Using clinical trial data, we show no difference in response to IO from testosterone. Similarly, our preclinical data show no IO response effect from gonadal castration. But 0.1 mg estradiol (E2) improves response in castrated male mice to that of female mice. Our overall objective is to understand how the premenopausal female hormone E2 contributes to progression and treatment resistance. Our data show that E2 had no effect on cancer cell viability, suggesting the tumor microenvironment (TME) as the site of action. E2 is known to play a major role in autoimmunity and inflammation, where it modulates dendritic cell (DC) and regulatory T cells (Treg) differentiation and function, and lymphatic vessel maturation. These immune cell populations regulate response to immunotherapy in HNSCC, but how they are affected by sex hormones remains largely uncharacterized. Our preclinical data also show that compared to male mice, females have increased DCs, less suppressive Tregs, and respond better to immunotherapeutic strategies with enhanced Teff function. Such response is removed with oophorectomy (OVX) but rescued with E2 of 0.1mg. OVX also changes the TME towards an immunosuppressive one with enhanced immunosuppressive Treg activity, similar to that of male mice. Finally, within the TME, OVX reduces the formation of high endothelial venules (HEVs) in the TME and draining lymph nodes (dLN), which enhance Teff cell priming and subsequent trafficking into the TME. We hypothesize that the sexually dimorphic response is driven by E2 acting via its receptors on Tregs and DCs to enhance antigen presentation and increase Teff activation, thus selectively determining response to immunotherapy. We also hypothesize that E2 will increase homing and trafficking of antigen specific T cells by enhancing HEV formation and maturation. In Aim1, we will interrogate the regulatory mechanisms of E2's effects on the DC biology by using genetically engineered mouse models (GEMMS), in vitro assays, and proteomic analysis to examine receptor subtypes and molecular mediators of DC differentiation, maturation, and antigen presentation. Aim 2 will dissect mechanisms of how E2's effect on Tregs can drive response and selection of sex-specific immunotherapies. We will test this with GEMMS, mouse chimeras, and pharmacological manipulation in in vivo and in vitro co-culture experiments, to identify signaling and downstream effectors. Focusing on T cell trafficking in Aim 3, we will examine E2's effect on HEV formation, and T cell egress from the dLN to the TME and systemic circulation using a combination of flow and immunofluorescence techniques in GEMMs and in vitro systems. These studies will collectively elucidate the basic mechanisms for advancing sex- directed novel biomarkers and therapeutics in HNSCC.

抽象的头颈癌（HNSCC）主要困扰男性。发生 HNSCC 的女性患者往往绝经后，绝经期激素治疗可降低罹患该疾病的风险。我们表明绝经前女性 HNSCC 患者对免疫治疗 (IO) 等治疗的反应有所改善。使用临床试验数据，我们显示睾酮对 IO 的反应没有差异。同样，我们的临床前数据性腺去势没有显示 IO 反应效应。但 0.1 毫克雌二醇 (E2) 可以改善去势患者的反应雄性小鼠与雌性小鼠的情况。我们的总体目标是了解绝经前女性激素如何 E2 有助于进展和治疗抵抗。我们的数据显示E2对癌细胞没有影响活力，表明肿瘤微环境（TME）是作用位点。众所周知，E2 在以下方面发挥着重要作用：自身免疫和炎症，它调节树突状细胞 (DC) 和调节性 T 细胞 (Treg) 分化和功能以及淋巴管成熟。这些免疫细胞群调节反应 HNSCC 的免疫疗法，但它们如何受到性激素的影响仍然很大程度上未知。我们的临床前数据还显示，与雄性小鼠相比，雌性小鼠的 DC 增加，抑制性 Tregs 减少，并通过增强 Teff 功能对免疫治疗策略做出更好的反应。此类回复已删除卵巢切除术 (OVX)，但用 0.1mg 的 E2 挽救。 OVX 还将 TME 转变为免疫抑制性Treg 活性增强，与雄性小鼠相似。最后，在 TME 内，OVX 减少 TME 中高内皮微静脉 (HEV) 的形成和引流淋巴液节点（dLN），增强 Teff 细胞启动和随后进入 TME 的运输。我们假设性二态性反应是由 E2 驱动的，E2 通过其在 Tregs 和 DC 上的受体发挥作用，以增强抗原呈递并增加 Teff 激活，从而选择性地确定对免疫疗法。我们还假设 E2 将增加抗原特异性 T 的归巢和运输细胞通过增强 HEV 的形成和成熟。在目标1中，我们将质疑监管机制通过使用基因工程小鼠模型 (GEMMS)、体外测定和研究 E2 对 DC 生物学的影响蛋白质组学分析可检查 DC 分化、成熟和发育的受体亚型和分子介质抗原呈递。目标 2 将剖析 E2 对 Tregs 的影响如何驱动反应和选择性别特异性免疫疗法。我们将用 GEMMS、小鼠嵌合体和药理学来测试这一点在体内和体外共培养实验中进行操作，以确定信号传导和下游效应器。重点关注目标 3 中的 T 细胞贩运，我们将研究 E2 对 HEV 形成的影响，以及 T 细胞从使用流式和免疫荧光技术相结合，将 dLN 输送至 TME 和体循环 GEMM 和体外系统。这些研究将共同阐明促进性行为的基本机制。指导 HNSCC 的新型生物标志物和治疗方法。