T cell responses shared among triple negative breast cancer patients

项目总结/摘要 三阴性乳腺癌（TNBC;雌激素受体，孕激素受体和HER2阴性）是乳腺癌的主要类型。 最致命的乳腺癌亚型然而，相对于其他乳腺癌亚型， 肿瘤浸润性T细胞这些T细胞的存在表明对肿瘤相关免疫反应的应答。 抗原从这种应答中，一些肿瘤特异性T细胞增殖并分化为效应细胞， 中央或组织驻留记忆T细胞。中央记忆T细胞寿命长， 检测身体中的有害抗原博尔赫斯博士和其他人最近表明， TNBC的死亡率在诊断后5年急剧下降。但不知道哪些患者会 对治疗有成功反应以及哪些患者会复发。因此，迫切需要确定 这些T细胞可以用于未来的治疗。本文提出鉴定以下共有的T细胞受体： 五年或五年以上的TNBC幸存者和正在接受治疗的患者。提出的总体目标 研究是使用最近由Slansky开发的方法来改善TNBC患者的治疗， 德科斯基实验室。他们使用高通量测序进行了研究，发现一组TCR共同 HLA-A2+乳腺癌患者，但不是健康对照。肿瘤中共有的T细胞受体也是 在这些患者的外周血中发现。此应用程序的总体目标是使用 α-β记忆性CD8 T细胞库用于鉴定应答患者中共有的T细胞应答 并确定标准疗法对T细胞的影响。这里讨论的中心假设是， 可以鉴定出TNBC幸存妇女血液中特有的常见TCR亚群 超过5年，但没有血液的妇女谁复发。解决这一假设的具体目标是 （1）鉴定来自TNBC幸存者血液的共享记忆T细胞的T细胞受体，和（2） 确定记忆T细胞库的纵向变化，这些变化与病理性的完全免疫相关。 治疗后的反应。使用T细胞库了解长期记忆的产生 对TNBC的反应可能最终会彻底改变TNBC的治疗，因为它将为TNBC的治疗提供第一步。 鉴定可用于确定维持无疾病的关键抗原的T细胞受体 生存和其他治疗，可以提供持续的保护，防止复发多年的生存。

PROJECT SUMMARY/ABSTRACT Triple negative breast cancer (TNBC; estrogen receptor-, progesterone receptor- and HER2-negative) is the deadliest sub-type of breast cancer. However, relative to other breast cancer sub-types, TNBCs can be found with many tumor infiltrating T cells. The presence of these T cells suggests a response to tumor-associated antigens. From this response, some of the tumor-specific T cells proliferate and differentiate into effector, central, or tissue-resident memory T cells. The central memory T cells are long-lived and can be found surveying the body for the offending antigens. It was recently shown by Dr. Borges and others that the risk of mortality from TNBC sharply decreases 5 years after diagnosis. However, it is unknown which patients will respond successfully to therapy and which patients will recur. Thus, there is an urgent need to determine how these T cells can be harnessed for future therapies. It is proposed here to identify shared T cell receptors of TNBC survivors of five or more years and patients undergoing therapy. The overall goal of the proposed research is to improve treatments for TNBC patients using a method recently developed by the Slansky and DeKosky labs. They performed studies using high throughput sequencing, and found a panel of TCRs common to HLA-A2+ breast cancer patients, but not healthy controls. The T cell receptors shared in tumors were also identified in the peripheral blood of these patients. The overall objective of this application is to use the repertoire of alpha-beta memory CD8 T cells to identify a shared T cell response among responder patients and to determine the influence of standard therapy on T cells. The central hypothesis addressed here is that common subsets of TCRs can be identified that are unique to the blood of women who have survived TNBC more than 5 years, but not blood of women who have recurred. The specific aims to address this hypothesis are: (1) to identify T cell receptors of shared memory T cells from the blood of TNBC survivors, and (2) determine longitudinal changes in the memory T cell repertoire that correlate with a pathologic complete response after treatment. Using the T cell repertoire to understand the generation of long-term memory responses to TNBC may ultimately revolutionize treatment for TNBC, as it will provide the first steps toward identification of T cell receptors that may be used to determine antigens critical to maintaining disease-free survival and other therapies that can offer ongoing protection against recurrence for years into survivorship.