Synergized Immune and Tumor Cell Bone Marrow Biomarkers to Predict Recurrence in Triple Negative Breast Cancer

项目总结/摘要 三阴性乳腺癌（TNBC）是侵袭性的，很大比例的患者发生转移性乳腺癌。 疾病在TNBC患者的骨髓（BM）中发现的播散性肿瘤细胞（DTC）可能是TNBC患者的肿瘤细胞。 转移过程的中间体。我们实验室和其他实验室的数据表明， BM的浓度可能影响DTC的潜伏期、治疗抗性和转移潜力。我们已经定义了， 验证了基于8种基因表达的生物标志物组，可检测未经治疗的TNBC BM中的DTC 患者，并预测远处转移性疾病的发展。我们最近的数据表明，TNBC患者 DTC阳性BM的免疫细胞前体群体发生改变，这与复发性 疾病发展。基于这些发现，我们假设免疫检查点抑制剂将 通过改变TNBC患者的免疫微环境，促进TNBC患者BM DTCs的消除 具有特异性DTC和/或BM免疫细胞群的患者，并且该细胞群特异性基因 表达特征可以预测哪些患者将从积极的免疫治疗中获益最多， 防止转移性疾病复发。 我们将使用我们从TNBC患者中收集的BM标本的广泛生物储存库来测试这一假设 接受常规化疗的患者，以及前瞻性收集的TNBC患者标本 参与独立资助的机构II期免疫检查点抑制剂（ICI）试验， 卡铂/紫杉醇/纳武单抗与或不与cabiralizumab。我们的目标是：1.为了评估我们8- 基因DTC基因面板，以预测参加我们的ICI治疗的TNBC患者的远处疾病发展 卡铂/紫杉醇/纳武单抗与或不与cabiralizumab的试验; 2.了解具体 用常规化疗和ICI治疗的TNBC患者中的BM DTC亚群， 对治疗有抗性，以及; 3.了解特异性T细胞和常规树突状细胞（cDC）的变化 当DTC存在时，BM中的人群，以及常规和ICI治疗对其的影响。的 这一建议的结果将导致更好地理解免疫逃逸和骨髓异质性 本发明的目的是提供用于改善TNBC患者中的常规和ICI疗法的微转移性疾病以及生物标志物。

Project Summary/Abstract Triple negative breast cancer (TNBC) is aggressive and a large percentage of patients develop metastatic disease. Disseminated tumor cells (DTCs) found in the bone marrow (BM) of TNBC patients may be the intermediaries of the metastatic process. Data from our lab as well as others suggest that the immune landscape of BM may influence DTC latency, treatment resistance, and metastatic potential. We have already defined and validated an 8 gene expression-based biomarker panel that can detect DTCs in the BM of treatment naïve TNBC patients and that predicts development of distant metastatic disease. Our recent data indicate that TNBC patients with DTC-positive BM have altered populations of immune cell precursors and this is associated with recurrent disease development. Based on these findings, we hypothesize that immune checkpoint inhibitors will facilitate the elimination of BM DTCs in TNBC patients by altering the immune microenvironment in patients with specific DTC and/or BM immune cell populations, and that cell population-specific gene expression signatures can predict which patients will benefit most from aggressive immunotherapy to prevent metastatic disease relapse. We will test this hypothesis using our extensive biorepository of BM specimens collected from TNBC patients who received conventional chemotherapy, as well as prospectively collected specimens from TNBC patients participating in an independently funded institutional phase II immune checkpoint inhibitor (ICI) trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab. Our goals are: 1. To evaluate the ability of our 8- gene DTC gene panel to predict distant disease development in TNBC patients enrolled in our ICI therapeutic trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab; 2. To understand the specific subpopulations of BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy which are resistant to therapy, and; 3. To understand alterations in specific T cell and conventional dendritic cell (cDC) populations in the BM when DTCs are present, and how this is impacted by conventional and ICI therapy. The results of this proposal will lead to a greater understanding of immune escape and heterogeneity of BM micrometastatic disease as well as biomarkers for improving conventional and ICI therapy in TNBC patients.