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

摘要 髓系来源的抑制细胞(MDSC)在荷瘤宿主中的扩增已成为一种主要的 限制保护性抗肿瘤T细胞反应的机制和癌症成功的主要障碍 免疫疗法。因此，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抑制作用。我们最近的研究表明，MDSC长期存在 激活一个称为未折叠蛋白反应(UPR)的整合信号网络，作为对 肿瘤的不稳定状态导致持续和明显的内质网(ER)应激 微环境(TME)。此外，有条件地删除UPR相关的PKR样ER激酶(PERK)的功能 将MDSC重新编程为免疫刺激细胞，部分恢复肿瘤保护性抗肿瘤免疫 床。重要的是，我们的新的初步结果表明，高度免疫- 肿瘤PERK消融术中调节初级和次级胆汁酸(Bas)。BA是在 肝脏和肠道作为胆固醇代谢的最终产物和通过启动法尼类X受体而发出的信号 (FXR)转录因子，在perk-空MDSC中发现增加，并增强MDSC抑制 活动。基于这些重要的发现，我们假设细胞内bas的积累限制了 肿瘤中PERK缺失的MDSC向髓系细胞的转化促进持续保护性T细胞免疫 通过激活FXR和随后诱导补偿的UPR介体，IRE1→XBP1。我们 同时提出抑制PERK+IRE1MDSC将完全克服在肿瘤中的连锁抑制 并与T细胞和检查点免疫疗法协同作用。我们提出了以下具体目标： 在目标1中，我们将确定累积的BA在功能转换中的约束作用 PERK-Null MDSC进入髓系细胞，启动持续的保护性抗肿瘤T细胞免疫。 在目标2中，我们将阐明BAs抑制PERKKO MDSC在肿瘤中转化的机制。 在目标3中，我们将检验PERK和IRE1联合抑制完全克服mdsc的预测。 相关的免疫抑制和提高癌症免疫治疗的有效性。 在肿瘤床中驱动MDSC免疫抑制功能的代谢介质仍然很少 描述。因此，目标的发展将对该领域产生深远的影响，因为它证实了一个重大的 肿瘤靶向内质网应激后限制MDSC功能转化的代谢信号 调停员，津贴。此外，我们的建议将为开发新的治疗方法提供一个机械的理论基础 在荷瘤宿主中完全重新编程免疫抑制的骨髓生成的方法，这可能会 与癌症免疫治疗协同，为肿瘤-MDSC重新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.