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 该拨款申请旨在为 Courtney Swain 在医学博士-博士培训期间提供 F31-Diversity 支持。这 该提案的研究重点是建立一种机制，其中高血糖和刺猬（Hh）信号传导 在三阴性患者中共同调节 CD8+ T 细胞耗竭和调节性 T 细胞 (Treg) 免疫抑制 乳腺癌（TNBC）。乳腺癌继续威胁着美国和世界各地许多女性的生命 因为它占所有女性癌症病例的 30% 以上。此外，2 型糖尿病 (T2D) 是一种 发病率很高，大约四分之一的乳腺癌患者患有糖尿病，这会增加 治疗并发症并限制治疗选择。 TNBC 肿瘤在免疫学上是“冷”的，其特点是 细胞毒性群体的有限渗透和免疫抑制成分的丰度增加 原发肿瘤。 T2D 发病机制中的高血糖与 CD8+ T 细胞、淋巴细胞损伤有关 在肿瘤杀伤和免疫治疗反应及其耗竭过程中至关重要。在肿瘤挑战后， 产生免疫反应性 TCF1+ 干细胞样和 TCF1- 短暂效应 CD8+ T 细胞亚群。 人们发现这些 CD8+ T 细胞亚群在肿瘤控制中非常重要，尽管它们的表型和 早期衰竭的术语。值得注意的是，高血糖加剧了乳房中 Hh 信号失调 癌症。初步研究表明，高血糖和 Hh 信号传导可能协同驱动 乳腺肿瘤环境中功能失调的 CD8+ T 细胞耗竭。此外，Tregs 的存在 乳腺肿瘤发生与 TNBC 较差的预后相关。支持本提案的证据 强调 Hh 信号传导和高血糖都会损害 CD8+ T 细胞耗竭并促进 Treg 免疫抑制。然而，这些因素影响这些关键 T 细胞群的机制 未知。因此，本提案将应用 Hh 信号传导和高血糖的独特模型系统来 描述它们在 TNBC 中 CD8+ T 细胞和 Treg 活性中的作用。研究结果将提供更多相关性 联合 TNBC 疗法，特别是针对糖尿病乳腺癌患者这一独特的患者群体。 PI 拟议的培训计划由她的博士导师 Lalita Shevde-Samant 博士赞助。的目标 培训计划旨在为 PI 提供： (i) 使用独特的临床前模型进行严格的研究项目 糖尿病相关乳腺癌、新型基因工程小鼠以及肿瘤免疫串扰； (二) 开发免疫学和生物信息技术以及扩大负责任的培训的机会 研究行为、严谨性、可重复性和科学诚信原则； (iii) 科学丰富 和设备齐全的环境对于作为肿瘤学家科学家发展成功的职业生涯至关重要。鉴于此 该项目的重点是美国两大疾病挑战——乳腺癌和糖尿病——之间的相互作用 PI 将获得模范指导和坚实的基础，以发展成为一名非常有能力的医师科学家。