Bile acids restrict functional reprogramming of myeloid-derived suppressor cells in tumor beds

胆汁酸限制肿瘤床中骨髓源性抑制细胞的功能重编程

基本信息

批准号：
10693220
负责人：
Paulo Cesar Rodriguez
金额：
$ 36.92万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693220
关键词：
Ablation Automobile Driving Beds Bile Acids Cell Reprogramming Cell physiology Cells Cholesterol Cholesterol Homeostasis Chronic Development Effectiveness Endoplasmic Reticulum Foundations Goals Human Immune Immune Evasion Immune checkpoint inhibitor Immunity Immunosuppression Immunotherapy In Situ Individual Infiltration Interferons Intestines Knockout Mice Link Liver Liver Regeneration LoxP-flanked allele Malignant Neoplasms Mediating Mediator Metabolic Modeling Mus Myeloid Cells Myeloid-derived suppressor cells Myelopoiesis Phosphotransferases Proteins Publications Reaction Receptor Activation Receptor Signaling Regulation Role STAT1 gene Signal Transduction T cell response T-Lymphocyte Testing Therapeutic Transplantation Tumor Immunity Tumor Markers XBP1 gene anticancer treatment cancer immunotherapy cell transformation checkpoint therapy endoplasmic reticulum stress gut inflammation immune cell infiltrate immunogenic in vivo information gathering insight novel strategies novel therapeutic intervention programs protein folding receptor response success synergism therapeutically effective transcription factor tumor tumor growth tumor microenvironment type I interferon receptor uptake

项目摘要

ABSTRACT The expansion of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts has emerged as a primary mechanism to limit protective anti-tumor T cell responses and a major obstacle to the success of cancer immunotherapy. It is therefore imperative to develop new effective therapeutic strategies to overcome the immune restricting effects induced by MDSC in tumors. Our recent studies demonstrated that MDSC chronically activate an integrated signaling network known as the unfolded protein responses (UPR) as a reaction to the sustained and pronounced endoplasmic reticulum (ER) stress induced by the precarious conditions of the tumor microenvironment (TME). Also, conditional deletion of the UPR-related PKR-like ER kinase (PERK) functionally reprogrammed MDSC into immunostimulatory cells that partially restore protective anti-tumor immunity in tumor beds. Importantly, our new Preliminary Results demonstrate a compensatory accumulation of highly immune- regulatory primary and secondary bile acids (BAs) in PERK-ablated MDSC in tumors. BAs are synthetized in the liver and intestine as final products of cholesterol metabolism and signal through priming of farnesoid X receptor (FXR) transcription factor, which was found increased in PERK-null MDSC and augmented MDSC suppressive activity. Based on these crucial findings, we hypothesize that the accumulation of intracellular BAs restricts the transformation of PERK-null MDSC in tumors into myeloid cells that promote sustained protective T cell immunity through activation of FXR and a subsequent induction of the compensatory UPR mediators, IRE1→Xbp1. We also propose that inhibition of PERK plus IRE1 will completely overcome MDSC-linked suppression in tumors and synergize with T cell and checkpoint immunotherapies. We propose the following Specific Aims: In Aim 1, we will determine the restrictive action of the accumulated BAs in the functional transformation of PERK-null MDSC into myeloid cells that prime sustained protective anti-tumor T cell immunity. In Aim 2, we will elucidate the mechanisms whereby BAs restrict PERKKO MDSC transformation in tumors. In Aim 3, we will test the prediction that combined inhibition of PERK and IRE1 completely overcomes MDSC- associated immunosuppression and enhances the effectiveness of cancer immunotherapy. The metabolic mediators driving the immunosuppressive functionality of MDSC in tumor beds remain poorly described. Thus, development of the Aims will have a profound impact on the field by substantiating a major metabolic signal whereby tumors restrict the functional transformation of MDSC after targeting the ER stress mediator, PERK. Also, our proposal will provide a mechanistic rationale for the development of novel therapeutic approaches to entirely reprogram immunosuppressive myelopoiesis in tumor-bearing hosts, which is likely to synergize with cancer immunotherapy and provide new biomarkers for tumor-MDSC reprogramming.

抽象的在肿瘤宿主中的髓样衍生抑制细胞（MDSC）的扩展已成为主要的限制受保护的抗肿瘤T细胞反应的机制和癌症成功的主要障碍免疫疗法。因此，必须制定新的有效治疗策略来克服 MDSC在肿瘤中引起的免疫限制作用。我们最近的研究表明，MDSC长期存在激活称为展开蛋白质反应（UPR）的集成信号网络作为对由肿瘤的不稳定条件引起的持续和明显的内质网（ER）应激微环境（TME）。同样，有条件地缺失了与UPR相关的PKR样ER激酶（PERK）的功能缺失将MDSC重新编程为免疫刺激细胞，该细胞部分恢复了肿瘤中受保护的抗肿瘤免疫史地床。重要的是，我们的新初步结果表明，高度免疫的补偿性积累肿瘤中的PERK燃烧的MDSC中的调节性原发性和继发性胆汁酸（BAS）。 BAS合成肝脏和肠作为胆固醇代谢的最终产物，并通过启动法尼X X接收器启动（FXR）转录因子，发现在PERK-NULL MDSC中增加并增强MDSC抑制活动。基于这些关键发现，我们假设细胞内BAS的积累限制了肿瘤中的PERK-NULL MDSC转化为髓样细胞，以促进受保护的T细胞免疫通过激活FXR和随后的补偿性UPR介质IRE1→XBP1的诱导。我们还建议抑制PERK PLUSIRE1将完全克服肿瘤中MDSC连接的抑制并与T细胞和检查点免疫疗法协同作用。我们提出以下具体目标：在AIM 1中，我们将确定累积BAS在功能转换中的限制性作用将MDSC的PERK-NULL MDSC进入髓样细胞，这些细胞持续了持续受保护的抗肿瘤T细胞免疫。在AIM 2中，我们将阐明基本限制肿瘤中Perkko MDSC转化的机制。在AIM 3中，我们将测试将PERK和IRE1完全克服MDSC-组合抑制的预测相关的免疫抑制并增强了癌症免疫疗法的有效性。驱动MDSC在肿瘤床中的免疫抑制功能的代谢介质仍然很差描述。这一目标的发展将通过证实主要代谢信号，肿瘤限制靶向ER应力后MDSC的功能转化调解人，珀克。此外，我们的建议将为开发新疗法提供机械原理完全重新编程的肿瘤宿主中的免疫抑制髓鞘的方法，这很可能与癌症免疫疗法协同作用，并为肿瘤MDSC重编程提供新的生物标志物。