Investigating the impact of hyperglycemia on modulating T cell populations in breast cancer

研究高血糖对调节乳腺癌 T 细胞群的影响

• 批准号: 10750137
• 负责人: Courtney A Swain
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750137
• 关键词: Antigens; Antitumor Response; Applications Grants; Automobile Driving; Bioenergetics; Bioinformatics; Biological Assay; Biological Models; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Breast Carcinoma; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Control; Clinical; Combined Modality Therapy; Competence; Data; Diabetes Mellitus; Disease; Doctor of Philosophy; Environment; Erinaceidae; FOXP3 gene; Female; Foundations; Functional disorder; Genes; Genetically Engineered Mouse; Glucose Intolerance; Glycolysis; Goals; Hyperglycemia; Immune; Immunologics; Immunosuppression; Immunotherapy; Impairment; Infiltration; Investigation; Lymphocyte; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mentors; Mentorship; Metabolic; Metabolism; Metformin; Modeling; Morbidity - disease rate; Nomenclature; Non-Insulin-Dependent Diabetes Mellitus; Oncologist; Outcome; Pathogenesis; Patients; Peripheral; Phenotype; Physicians; Population; Pre-Clinical Model; Primary Neoplasm; Process; Production; Prognosis; Readiness; Regulatory T-Lymphocyte; Reporting; Reproducibility; Research; Research Project Grants; Risk; Role; Scientist; Solid; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Training; Type 2 diabetic; United States; Woman; Work; breast cancer progression; cancer infiltrating T cells; career; cytokine; cytotoxic; diabetic; diabetic patient; exhaustion; glycemic control; immunogenicity; malignant breast neoplasm; mammary; marginalized population; mouse model; novel; patient population; patient subsets; pre-clinical; programs; response; responsible research conduct; smoothened signaling pathway; stem; treatment and outcome; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenic

PROJECT ABSTRACT This grant application is for the F31-Diversity support of Courtney Swain during her MD-PhD training. The research focus of this proposal is to establish a mechanism in which hyperglycemia and Hedgehog (Hh) signaling conspire to modulate CD8+ T cell exhaustion and regulatory T cell (Treg) immunosuppression in triple-negative breast cancer (TNBC). Breast cancer continues to threaten the lives of many women in the U.S. and worldwide as it accounts for more than 30% of all female cancer cases. Additionally, type 2 diabetes mellitus (T2D) is a highly prevalent morbidity and about a quarter of breast cancer patients are diabetic, which can increase treatment complications and limit therapy options. TNBC tumors are immunologically “cold,” characterized by the limited infiltration of cytotoxic populations and increased abundance of immunosuppressive constituents in the primary tumor. Hyperglycemia in T2D pathogenesis has been implicated to impair CD8+ T cells, lymphocytes critical in tumor killing and immunotherapy response, and their exhaustion process. Upon tumor challenge, subsets of immunologically reactive TCF1+ stem-like and TCF1- transitory effector CD8+ T cells are generated. These CD8+ T cell subsets have been found to be highly essential in tumor control despite their phenotype and nomenclature of early exhaustion. Notably, hyperglycemia exacerbates dysregulated Hh signaling in breast cancer. Initial investigations have revealed that hyperglycemia and Hh signaling may be cooperatively driving dysfunctional CD8+ T cell exhaustion in the mammary tumor milieu. Additionally, the presence of Tregs during mammary tumorigenesis correlates with poorer prognoses in TNBC. Supporting evidence in this proposal underscores that both, Hh signaling and hyperglycemia, impair CD8+ T cell exhaustion and promote Treg immunosuppression. However, the mechanisms by which these factors influence these key T cell populations are unknown. Therefore, this proposal will apply unique model systems of Hh signaling and hyperglycemia to delineate their roles in CD8+ T cell and Treg activity in TNBC. Findings will provide more relevance for combination TNBC therapies, especially for the distinct patient population of diabetic breast cancer patients. The proposed training plan for the PI is sponsored by her PhD mentor, Dr. Lalita Shevde-Samant. The goals of the training plan are to provide the PI with: (i) a rigorous research project using distinctive pre-clinical models of diabetes-associated breast cancer, novel genetically engineered mice, and tumor-immune crosstalk; (ii) opportunities in developing immunologic and bioinformatic techniques and in expanding training in responsible conduct of research, rigor, reproducibility, and principles of scientific integrity; and (iii) a scientifically enriching and equipped environment essential for developing a successful career as an oncologist-scientist. Given this project’s focus on the interaction of two major disease challenges of the U.S., breast cancer and diabetes, the PI will have exemplary guidance and a solid foundation to develop into a very competent physician-scientist.

项目摘要 该赠款申请是在MD-PHD培训期间对Courtney Swain的F31多样性支持。这 该建议的研究重点是建立一种机制，高血糖和刺猬（HH）信号传导 合并调节三阴性的CD8+ T细胞耗尽和调节T细胞（TREG）免疫抑制 乳腺癌（TNBC）。乳腺癌继续威胁到美国和全球许多妇女的生命 因为它占所有女性癌症病例的30％以上。此外，2型糖尿病（T2D）是 高度普遍的发病率和大约四分之一的乳腺癌患者是糖尿病患者，可以增加 TNBC肿瘤在免疫学上是“冷”，其特征是 在 原发性肿瘤。 T2D发病机理中的高血糖已与CD8+ T细胞有关 对肿瘤杀伤和免疫疗法的反应至关重要及其疲惫过程。在肿瘤挑战时， 产生了免疫反应性TCF1+茎状和TCF1转换效应子CD8+ T细胞的子集。 这些CD8+ T细胞子集在肿瘤控制目的地中非常重要，它们的表型和 早期疲惫的命名法。值得注意的是，高血糖加剧了乳房中HH信号失调 癌症。最初的调查表明，高血糖和HH信号可能正在合作驱动 乳腺肿瘤环境中功能失调的CD8+ T细胞耗尽。另外，在 乳腺肿瘤发生与TNBC中较差的预后相关。该提议中的支持证据 强调HH信号传导和高血糖，都会损害CD8+ T细胞耗尽并促进Treg 免疫抑制。但是，这些因素影响这些关键T细胞种群的机制 是未知的。因此，该建议将应用HH信号传导和高血糖的独特模型系统 描述它们在TNBC中的CD8+ T细胞和Treg活性中的作用。调查结果将为 联合TNBC疗法，特别是针对糖尿病乳腺癌患者的不同患者群体。 PI的拟议培训计划由她的博士学位Lalita Shevde-Samant博士赞助。目标 培训计划将为PI提供：（i）使用独特的临床前模型的严格研究项目 糖尿病相关的乳腺癌，新型的基因工程小鼠和肿瘤免疫串扰； （ii） 开发免疫和生物信息学技术以及扩大负责任的培训的机会 进行研究，严格，可重复性和科学完整性原理的进行； （iii）科学丰富 以及为发展作为肿瘤学家科学家成功职业至关重要的设备环境。鉴于此 项目关注美国两种主要疾病挑战的相互作用，乳腺癌和糖尿病，即 PI将具有典范指导和坚实的基础，以发展成一个非常有能力的身体科学家。