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

项目摘要 此补助金申请是为F31-多样性支持考特尼斯温在她的MD-PhD培训。的 这项建议的研究重点是建立一个机制，其中高血糖和刺猬（Hh）信号 协同调节三阴性患者中CD 8 + 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（T2 D）是一种 高发病率和约四分之一的乳腺癌患者是糖尿病患者， 治疗并发症和限制治疗选择。TNBC肿瘤在免疫学上是“冷的”，其特征在于： 细胞毒性群体的有限浸润和免疫抑制成分的增加， 原发肿瘤。T2 D发病机制中的高脂血症涉及损害CD 8 + T细胞、淋巴细胞 在肿瘤杀伤和免疫治疗反应及其耗竭过程中至关重要。在肿瘤激发后， 产生免疫反应性TCF 1+干细胞样和TCF 1-瞬时效应CD 8 + T细胞的亚群。 已经发现这些CD 8 + T细胞亚群在肿瘤控制中是高度必需的，尽管它们的表型和 早期衰竭的命名法值得注意的是，高血糖症加剧了乳腺癌中Hh信号的失调， 癌初步研究表明，高血糖和Hh信号可能是协同驱动 乳腺肿瘤环境中功能失调的CD 8 + T细胞耗竭。此外，在治疗过程中， 乳腺肿瘤发生与TNBC中较差的乳腺癌相关。本提案中的支持证据 强调了Hh信号传导和高血糖症都损害了CD 8 + T细胞的耗竭，并促进了Treg 免疫抑制然而，这些因素影响这些关键T细胞群的机制 是未知的。因此，该提议将Hh信号传导和高血糖症的独特模型系统应用于 描述了它们在TNBC中的CD 8 + T细胞和Treg活性中的作用。调查结果将提供更多的相关性， 因此，本发明提供了用于TNBC联合疗法的方法，特别是用于糖尿病乳腺癌患者的不同患者群体。 PI的拟议培训计划由其博士导师Lalita Shevde-Samant博士赞助。的目标 培训计划将为PI提供：（i）使用独特的临床前模型进行严格的研究项目， 糖尿病相关的乳腺癌，新型基因工程小鼠和肿瘤免疫串扰;（ii） 发展免疫学和生物信息学技术以及扩大责任领域培训的机会 研究的进行、严谨性、可重复性和科学完整性原则;以及（iii）科学上丰富的 和装备的环境至关重要的发展一个成功的职业生涯作为一个肿瘤学家，科学家。鉴于这种 该项目的重点是美国两大疾病挑战的相互作用，乳腺癌和糖尿病， PI将有示范性的指导和坚实的基础，发展成为一个非常称职的医生，科学家。

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.