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.

抽象的这项补充是为了响应特殊利益通知（NOSI）而提交，被认为是非ca- 22-054。基于传统，补充和替代医学（TCAM）的治疗策略具有成为癌症的潜在治疗选择，尤其是在低收入和中等收入国家（LMIC）对高级技术的访问有限。但是，基于TCAM良好控制的影响在癌症患者保护性抗肿瘤免疫的调节仍然很差。髓样的扩张 - 含肿瘤宿主中的衍生抑制细胞（MDSC）代表了限制保护性抗抗性的主要机制肿瘤T细胞免疫和癌症免疫疗法成功的主要障碍。因此，这是当务之急制定新的有效治疗策略来克服MDSC在肿瘤。我们最近的研究表明，肿瘤中的MDSC激活了综合信号网络已知随着展开的蛋白质反应（UPR）作为对持续和明显内质网的反应（ER）由肿瘤微环境（TME）的不稳定条件引起的应力。此外，有条件与UPR相关的PKR样ER激酶（PERK）的删除功能重编程为免疫 - 部分恢复保护性抗肿瘤免疫力的刺激细胞。在相关的R01中，我们假设肿瘤宿主中胆汁酸（BAS）的积累限制了PERK开放的功能转化 MDSC。但是，人群中MDSC中BAS和ER应力轴的验证仍然未知。 P2ET是一种富含多酚的提取物，来自植物乳突的脊柱，通过激活促进抗肿瘤活性保护性免疫和直接抗肿瘤作用，都降低了肿瘤内MDSC的频率。虽然 P2ET诱导动物模型中的抗肿瘤作用，其在患者人群中的影响仍然未知。在这个补充说，我们的目标是与资助的I/II期临床研究相交，以测试P2ET对乳腺癌的影响（BC）在南美哥伦比亚接受新辅助化疗的患者进行了R01连接研究测试 MDSC经历了升高的ER应力激活和血浆BAS改变的影响。我们假设这一点接受P2ET作为治疗方案的一部分的患者将显示出急需的MDSC和较低的循环BAS水平与阳性治疗反应相关。我们提出以下内容特定目的：目标1。评估II-III阶段患者中循环MDSC和血浆BAS的扩展接受P2ET和新辅助治疗的治疗。目标2。确定循环中的改变是否 MDSC和血浆BAS预测用P2ET给药的II-III阶段BC患者的反应。拟议的研究将通过潜在地阐明ER应力和BAS轴的影响来提高母体RO1的范围来自癌症患者的MDSC，同时使LMIC的基于TCAM的策略驱动保护性免疫，但有可能克服癌症免疫疗法的实质性障碍。