Plant-derived extracts regulate immunosuppressive myelopoiesis in Breast cancer patients

植物提取物调节乳腺癌患者的免疫抑制性骨髓细胞生成

基本信息

批准号：
10622036
负责人：
Paulo Cesar Rodriguez
金额：
$ 21.06万
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/10622036
关键词：
Adjuvant American Indians Animal Model Bile Acids Binding Breast Cancer Patient Breast Cancer Treatment CD8B1 gene Caesalpinia Cancer Etiology Cancer Patient Caribbean region Catabolism Cell Death Cells Cessation of life Chinese Cholesterol Clinical Clinical Research Colombia Colombian Complementary and alternative medicine Complex Development Endoplasmic Reticulum Flow Cytometry Foundations Frequencies Funding Gallic acid Goals Hindu Human Immune Immune Evasion Immunity Immunosuppression Immunotherapy Indigenous Infrastructure Intestines Latin American Link Liver Malignant Neoplasms Mediating Metabolic Monitor Myelogenous Myeloid Cells Myeloid-derived suppressor cells Myelopoiesis Natural Products Neoadjuvant Therapy Neoplasm Metastasis Parents Patients Phase Phosphotransferases Placebos Plant Extracts Plants Plasma Population Prevention Primary Neoplasm Progression-Free Survivals Proteins Quality of life Reaction Research Role Sampling Signal Transduction Small Business Innovation Research Grant Small Business Technology Transfer Research South America T-Lymphocyte Technology Testing Therapeutic Treatment Protocols Tumor Immunity Validation antitumor effect base cancer cell cancer immunotherapy chemotherapy endoplasmic reticulum stress granulocyte immunogenic interest low and middle-income countries malignant breast neoplasm metabolomics monocyte mortality mouse model patient population polyphenol predicting response prevent receptor response success therapeutically effective transcription factor treatment response tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT This supplement is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-054. Therapeutic strategies based on traditional, complementary, and alternative medicine (TCAM) have emerged as a potential treatment option for cancer, especially in low- and middle-income countries (LMICs) with limited access to advanced technologies. However, the impact of well-controlled TCAM-based treatments in the modulation of protective anti-tumor immunity in cancer patients remains poorly defined. Expansion of myeloid- derived suppressor cells (MDSC) in tumor-bearing hosts represents a primary mechanism to limit protective anti- tumor T cell immunity 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 in tumors 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). Furthermore, conditional deletion of the UPR-related PKR-like ER kinase (PERK) functionally reprogrammed tumor-MDSC into immune- stimulatory cells that partially restore protective anti-tumor immunity. In the related R01, we postulate that the accumulation of Bile Acids (BAs) in tumor-bearing hosts restricts the functional transformation of PERK-ablated MDSC. However, the validation of the BAs and ER stress axis in MDSC in human populations remains unknown. P2Et, a polyphenol-rich extract from plant Caesalpinia spinosa, promotes anti-tumor activities through activation of protective immunity and direct anti-tumor effects, both reducing the frequency of intratumor MDSC. Although P2Et induces anti-tumor actions in animal models, its effect in patient populations remains unknown. In this supplement, we aim to intersect a funded Phase I/II clinical study testing the effect of P2Et in Breast cancer (BC) patients receiving neoadjuvant chemotherapy in Colombia, South America, with R01-linked research testing the effects of MDSC undergoing elevated ER stress activation and alterations in plasma BAs. We hypothesize that patients receiving P2Et as part of their treatment regimen will show reduced numbers of ER-stressed MDSC and lower levels of circulating BAs, which associate with positive therapeutic responses. We propose the following Specific Aims: Aim 1. Evaluate the expansion of circulating MDSC and plasma BAs in stage II-III BC patients undergoing treatment with P2Et plus neoadjuvant therapy. Aim 2. Determine whether alterations in circulating MDSC and plasma BAs predict responses in stage II-III BC patients administered with P2Et. Proposed research will advance the scope of the parent RO1 by potentially elucidating the effects of the ER stress and BAs axis in MDSC from cancer patients, while enabling TCAM-based strategies in LMICs to drive protective immunity, potentially overcoming a substantial obstacle for cancer immunotherapies.

抽象的本补充材料是为了响应被确定为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 22-054。基于传统医学、补充医学和替代医学 (TCAM) 的治疗策略成为癌症的潜在治疗选择，特别是在低收入和中等收入国家（LMIC）获得先进技术的机会有限。然而，良好控制的基于 TCAM 的治疗对癌症患者保护性抗肿瘤免疫的调节仍然不明确。髓系扩张- 荷瘤宿主中的衍生抑制细胞（MDSC）代表了限制保护性抗肿瘤的主要机制。肿瘤T细胞免疫是癌症免疫治疗成功的主要障碍。因此势在必行开发新的有效治疗策略来克服 MDSC 引起的免疫限制作用肿瘤。我们最近的研究表明肿瘤中的 MDSC 激活已知的整合信号网络作为未折叠蛋白反应（UPR）作为对持续且明显的内质网的反应 (ER) 应激是由肿瘤微环境 (TME) 的不稳定条件引起的。此外，有条件的删除 UPR 相关 PKR 样 ER 激酶 (PERK) 功能性地将肿瘤 MDSC 重编程为免疫 MDSC 刺激细胞部分恢复保护性抗肿瘤免疫力。在相关的 R01 中，我们假设荷瘤宿主体内胆汁酸 (BA) 的积累限制了 PERK 消除的功能转化 MDSC。然而，人类 MDSC 中 BA 和 ER 应激轴的验证仍然未知。 P2Et 是一种来自刺实云实 (Caesalpinia spinosa) 的富含多酚的提取物，通过激活促进抗肿瘤活性保护性免疫和直接抗肿瘤作用，均降低瘤内 MDSC 的频率。虽然 P2Et 在动物模型中诱导抗肿瘤作用，但其对患者群体的影响仍不清楚。在这个补充，我们的目标是交叉资助一项 I/II 期临床研究，测试 P2Et 对乳腺癌 (BC) 的影响在南美洲哥伦比亚接受新辅助化疗的患者，与 R01 相关的研究测试了 MDSC 经历升高的 ER 应激激活和血浆 BA 改变的影响。我们假设接受 P2Et 作为治疗方案一部分的患者将表现出 ER 应激性 MDSC 数量减少，并且循环 BA 水平较低，这与积极的治疗反应相关。我们提出以下建议具体目标：目标 1. 评估 II-III 期 BC 患者循环 MDSC 和血浆 BA 的扩增正在接受 P2Et 加新辅助治疗的治疗。目标 2. 确定循环中是否发生变化 MDSC 和血浆 BA 可以预测服用 P2Et 的 II-III 期 BC 患者的反应。拟议的研究将通过潜在地阐明 ER 应力和 BAs 轴的影响来推进母体 RO1 的范围来自癌症患者的 MDSC，同时使中低收入国家基于 TCAM 的策略能够驱动保护性免疫，有可能克服癌症免疫疗法的重大障碍。