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

摘要 骨髓源性抑制细胞（MDSC）在荷瘤宿主中的扩增已成为肿瘤发生的主要原因。 限制保护性抗肿瘤T细胞反应的机制和癌症治疗成功的主要障碍 免疫疗法因此，迫切需要开发新的有效的治疗策略来克服 MDSC在肿瘤中诱导的免疫限制作用。我们最近的研究表明，MDSC慢性 激活一个被称为未折叠蛋白反应（UPR）的整合信号网络， 持续和明显的内质网（ER）应激诱导的不稳定的条件下的肿瘤 微环境（TME）。此外，UPR相关的PKR样ER激酶（PERK）的功能性条件性缺失， 将MDSC重编程为免疫刺激细胞，其部分恢复肿瘤中的保护性抗肿瘤免疫 床重要的是，我们新的初步结果表明，高免疫性的代偿性积累- 调节性初级和次级胆汁酸（BA）在肿瘤中的PERK消融的MDSC中的作用。BA是在 肝和肠作为胆固醇代谢的终产物和通过法尼醇X受体引发的信号 (FXR)在PERK缺失的MDSC中发现转录因子增加， 活动基于这些重要的发现，我们假设细胞内BA的积累限制了细胞内的代谢。 肿瘤中PERK-无效MDSC转化为促进持续保护性T细胞免疫的髓样细胞 通过激活FXR和随后诱导代偿性UPR介质，IRE 1 → Xbp 1。我们 我还提出，抑制PERK加IRE 1 β将完全克服肿瘤中MDSC相关的抑制作用， 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： 在目标1中，我们将确定累积的BA在功能转换中的限制作用， PERK无效MDSC进入骨髓细胞，引发持续的保护性抗肿瘤T细胞免疫。 在目标2中，我们将阐明BA限制肿瘤中PERKKO MDSC转化的机制。 在目标3中，我们将测试PERK和IRE 1的组合抑制完全克服MDSC的预测。 相关的免疫抑制和增强癌症免疫治疗的有效性。 代谢介质驱动MDSC在肿瘤床中的免疫抑制功能仍然很差 介绍了因此，目标的制定将对该领域产生深远的影响， 代谢信号，由此肿瘤在靶向ER应激后限制MDSC的功能转化 调解员，津贴。此外，我们的建议将提供一个机制的理由，为发展新的治疗 在肿瘤宿主中完全重编程免疫抑制性骨髓生成的方法， 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。

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.