权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Steroid hormone regulation of immune responses

类固醇激素对免疫反应的调节

基本信息

批准号：
10189531
负责人：
ANA C ANDERSON
金额：
$ 38.4万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189531
关键词：
Ablation Affect Antibodies CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cholesterol Chronic Data Development Dissection Enzymes Exhibits Functional disorder Generations Genes Glucocorticoid Receptor Glucocorticoids Goals Grant Immune Immune response Immune system Immunosuppression Immunosuppressive Agents In Vitro Inflammatory Interleukin-10 Knockout Mice Knowledge Laboratories Ligands MT3 gene Malignant Neoplasms Mediator of activation protein Metabolism Metallothionein Molecular Molecular Target Morbidity - disease rate Mus NR3C1 gene Phenotype Play Positioning Attribute Pregnenolone Process Production Proteins Receptor Signaling Role Signal Transduction Source Steroids T cell response T-Lymphocyte Tumor Immunity Tumor Tissue Tumor-Infiltrating Lymphocytes Tumor-associated macrophages Work Zinc Zinc Fingers anti-cancer anti-tumor immune response base conditional knockout cytokine cytotoxic cytotoxicity effector T cell exhaust fighting hormonal signals immunoregulation improved in vivo mortality novel novel strategies novel therapeutics programmed cell death protein 1 programs receptor receptor expression steroid hormone synergism tool transcription factor tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Signals present within the tumor microenvironment (TME) undermine the ability of the immune system to fight cancer. In particular, these signals together with chronic stimulation disable effector CD8+ T cell responses by promoting the development of a dysfunctional or “exhausted” T cell state. As dysfunctional CD8+ T cells are defective in their ability to elicit cytotoxicity and produce pro-inflammatory cytokines, they are poor mediators of tumor clearance. Moreover, dysfunctional CD8+ T cells can produce IL-10, indicating that they can also contribute to immune suppression with the TME. Thus, dysfunctional CD8+ T cells present not only an obstacle but also a liability for the generation of productive anti-tumor immunity. Accordingly, understanding both the T cell intrinsic and extrinsic signals that promote dysfunctional phenotype is of key importance in devising novel therapies to improve anti-cancer T cell responses. We have examined the gene programs underlying T cell dysfunction in CD8+ tumor-infiltrating lymphocytes (TILs). We have thus discovered that NR3C1, the gene encoding the glucocorticoid receptor (GR), is preferentially expressed by CD8+ TILs that exhibit severe dysfunctional phenotype. Glucocorticoids (GCs) are steroid hormones and ligands for GR. Although both natural and synthetic glucocorticoids are known to be potent immune-suppressive agents, the precise molecular mechanisms by which they suppress effector T cell responses are poorly understood. Our preliminary data indicate that GC-GR signaling is indeed active in CD8+ TILs and that tumor-associated macrophages (TAMs) are a local source of steroid in the TME. We further find that mice that lack expression of NR3C1 specifically in CD8+ T cells exhibit improved tumor growth control and that NR3C1-deficient CD8+ TILs exhibit improved effector function concomitant with dramatically reduced expression of co-inhibitory receptors such as Tim-3 and PD-1. In line with these data, we find that GC-GR signaling promotes co-inhibitory receptor expression and dampens both the cytotoxic capacity and pro-inflammatory cytokine production of CD8+ T cells in vitro. Interestingly, we find that GC-GR signaling potently synergizes with the immunoregulatory cytokine IL-27 to further augment the expression of co-inhibitory receptors and dampen pro-inflammatory cytokine production and cytotoxic capacity in CD8+ T cells while concomitantly inducing IL-10 production. Based on our preliminary data, we hypothesize that GC-GR signaling is a key component of the immune suppressive network in the TME that disables anti-tumor T cell responses by: 1) direct promotion of dysfunction-associated gene programs in effector T cells; and 2) synergizing with signals in the TME such as IL-27. We propose the following specific aims: 1) Molecularly dissect the role of steroid signaling in CD8+ and CD4+ T cells in the TME and 2) Define the GC-GR signaling circuit and the basis for synergy with IL-27 in immune- suppression in the TME.

项目总结