T cell responses shared among triple negative breast cancer patients

三阴性乳腺癌患者共有 T 细胞反应

• 批准号: 9767747
• 负责人: Jill E Slansky
• 金额: $ 16.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767747
• 关键词: Address; Aftercare; Animal Model; Antigens; Antitumor Response; Blood; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer survivor; CD8-Positive T-Lymphocytes; Cancer Burden; Cessation of life; Characteristics; Clinical; Diagnosis; Disease; Disease-Free Survival; ERBB2 gene; Estrogen Receptors; Estrogens; Future; Generations; Goals; HLA-A2 Antigen; High-Throughput Nucleotide Sequencing; Human; Immune; Immune system; Immunotherapy; In complete remission; Knowledge; Life; Maintenance; Memory; Methods; Mission; Monitor; Mutate; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Outcome; Pathologic; Patients; Predictive Value; Progesterone; Progesterone Receptors; Proliferating; Public Health; Recurrence; Research; Residual Cancers; Risk; Specificity; Surveys; Survivors; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Treatment outcome; Tumor Antigens; United States National Institutes of Health; Vaccines; Woman; antigen-specific T cells; breast cancer diagnosis; cancer subtypes; chemotherapy; design; effective therapy; immunotherapy clinical trials; improved; long term memory; malignant breast neoplasm; melanoma; mortality; mortality risk; neoantigens; outcome forecast; overtreatment; peripheral blood; prognostic value; receptor; response; shared memory; survivorship; triple-negative invasive breast carcinoma; tumor; vaccine development

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.

项目摘要/摘要 三阴性乳腺癌(TNBC；雌激素受体、孕激素受体和HER2阴性)是 最致命的乳腺癌亚型。然而，相对于其他乳腺癌亚型，可以发现TNBCs 有许多肿瘤浸润性T细胞。这些T细胞的存在表明对肿瘤相关的反应 抗原。在这种反应中，一些肿瘤特异性T细胞增殖并分化为效应器， 中央或组织驻留的记忆T细胞。中央记忆T细胞寿命很长，可以找到 检查身体中是否有令人不快的抗原博尔赫斯博士和其他人最近表明， 确诊5年后，TNBC的死亡率急剧下降。然而，目前还不清楚哪些患者会 对治疗成功的反应以及哪些患者会复发。因此，迫切需要确定如何 这些T细胞可以被用于未来的治疗。在此，我们建议鉴定共享的T细胞受体 五年或以上的TNBC幸存者和正在接受治疗的患者。建议的总体目标是 研究是使用Slansky最近开发的一种方法来改进对TNBC患者的治疗 德科斯基实验室。他们使用高通量测序进行研究，发现一组共同的TCR 人类白细胞抗原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液中发现。此应用程序的总体目标是使用 识别应答患者共享T细胞应答的α-β记忆CD8 T细胞谱系 并确定标准治疗对T细胞的影响。这里讨论的中心假设是 可以确定TCR的常见亚群，这些亚群是在TNBC中存活的女性血液中独有的 超过5年，但没有复发妇女的血液。具体的目的是为了解决这一假设 (1)从TNBC幸存者的血液中鉴定共享记忆T细胞的T细胞受体；(2) 确定与病理完整相关的记忆T细胞谱系的纵向变化 治疗后反应。利用T细胞谱系理解长时记忆的产生 对TNBC的反应最终可能使TNBC的治疗发生革命性变化，因为它将为实现以下目标迈出第一步 可用于确定对维持无病至关重要的抗原的T细胞受体的鉴定 生存和其他治疗方法，可以提供持续的保护，防止存活多年后复发。