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

项目摘要 这项资助申请是为了考特妮·斯温在她的医学博士培训期间提供的F31-多样性支持。这个 本方案的研究重点是建立高血糖和Hedgehog(HH)信号转导机制 合谋调节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 发病率很高，大约四分之一的乳腺癌患者患有糖尿病，这可能会增加 治疗并发症和限制治疗选择。TNBC肿瘤在免疫上是“冷的”，其特征是 细胞毒群体的有限渗透和免疫抑制成分的增加 原发肿瘤。T2D发病机制中的高血糖与CD8+T细胞、淋巴细胞受损有关 在肿瘤杀伤和免疫治疗反应以及它们的耗尽过程中至关重要。在肿瘤挑战中， 产生免疫反应性TCF1+干细胞型和TCF1-暂时性效应CD8+T细胞亚群。 这些CD8+T细胞亚群被发现在肿瘤控制中非常重要，尽管它们的表型和 早期精疲力竭的命名。值得注意的是，高血糖加剧了乳房HH信号的失调。 癌症。初步研究表明，高血糖和HH信号可能是协同驱动的 乳腺肿瘤环境中功能障碍的CD8+T细胞耗竭。此外，Tregs的存在在 在TNBC中，乳腺肿瘤的发生与预后较差有关。本建议书中的支持性证据 强调HH信号和高血糖都会损害CD8+T细胞的耗竭并促进Treg 免疫抑制。然而，这些因素影响这些关键T细胞群体的机制 都是未知的。因此，这项建议将应用独特的HH信号和高血糖模型系统来 阐明它们在TNBC中CD8+T细胞和Treg活性中的作用。调查结果将为以下方面提供更多相关性 TNBC联合治疗，特别是针对糖尿病乳腺癌患者的不同患者群体。 提议的国际和平协会的培训计划是由她的博士导师Lalita Shevde-Samant博士赞助的。的目标 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 糖尿病相关乳腺癌、新型基因工程小鼠和肿瘤免疫串扰； 发展免疫学和生物信息学技术以及扩大责任人培训的机会 研究的进行、严谨性、再现性和科学完整性原则；以及(Iii)科学丰富 并配备了作为肿瘤学家和科学家发展成功职业生涯所必需的环境。鉴于此， 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， 少年派将拥有模范的指导和坚实的基础，以发展成为一名非常称职的内科科学家。

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.