Strategies to improve outcomes for TNBC patients that integrate subtype-specific genomic and immune-based discoveries

项目摘要/摘要：改善跨国公司成果的战略 整合亚型特异性基因组和基于免疫的发现的患者 三阴性乳腺癌(TNBC)是乳腺癌中最具侵袭性的亚型之一， 约25%的乳腺癌死亡是由于缺乏有效的治疗方法。为了应对这一挑战，我们的团队 分子遗传学、肿瘤学和生物信息学方面的综合专业知识，以及1)将TNBC分类为不同的 具有独特的信号、生物和免疫功能的分子亚型；2)发现并验证 致癌基因和免疫调节基因中的新基因重排提供了不同的 TNBC肿瘤逃避免疫监视的机制。许多肿瘤细胞选择先天的和适应性的 通过直接上调PD-L1或通过免疫募集的免疫系统机制 抑制性细胞。这些形式的免疫逃避在基因突变负担高的肿瘤中发挥着作用， 例如选择TNBC子类型。在目前的时期，我们发现一些TNBC高的肿瘤 由于肿瘤中缺乏免疫细胞和免疫功能的增强，突变负荷仍保持“免疫冷”状态 微环境中的抑制性细胞。针对PD-1/PD-L1途径的免疫疗法继续 治疗高突变率转移性癌症的范式转变，因此理解 如何使合适的TNBC患者与这一治疗进展保持一致。AS联合化疗和免疫治疗 FDA批准转移性TNBC的进展，进一步催化了了解其特异性的必要性 化疗药物可依次增强抗PD-1/PD-L1治疗的TNBC亚型特异性应答 以确定最有效的组合。化疗调节的机制 TNBC中的新抗原负荷、T细胞功能和免疫抑制细胞功能在很大程度上是未知的。我们 建议检验以下相关假设：(1)标准化疗可调节肿瘤 抗PD-L1治疗以TNBC亚型特异性方式靶向的免疫反应；以及(2)亚型特异性 TNBC临床前模型将提供对化疗特定的全身和肿瘤微环境的洞察 免疫抑制的机制。该项目的具体目标是：目标1：通过以下方式确定机制 哪些标准化疗药物结合检查点调节肿瘤免疫反应 免疫治疗；目标2：确定肿瘤分泌蛋白质和外切体的机制 调节转移性TNBC亚型的免疫系统；和目标3：评估靶向治疗的可行性 肿瘤微环境中髓系来源的细胞。影响：我们的总体目标是改善TNBC的结果 患者通过对TNBC亚型和TBC亚型的知识指导的联合治疗 免疫调节功能。通过对生物菌群的综合分析，我们建立了多个生物群。 学科团队将开发PD-L1反应的生物标记物，并确定化疗对 不同的免疫细胞群。新的免疫逃避机制的发现将导致可诉讼的 影响转移性TNBC和其他乳腺癌的未来药物发现努力的分子靶点。

PROJECT SUMMARY/ABSTRACT: STRATEGIES TO IMPROVE OUTCOMES FOR TNBC PATIENTS INTEGRATING SUBTYPE-SPECIFIC GENOMIC AND IMMUNE-BASED DISCOVERIES Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, representing ~25% of all breast cancer deaths due to lack of effective therapies. To address this challenge, our team integrated expertise in molecular genetics, oncology and bioinformatics, and 1) classified TNBC into distinct molecular subtypes with unique signaling, biologic and immune features, and 2) discovered and validated novel gene rearrangements in oncogenic and immune-regulatory genes that provide a diverse array of mechanisms by which TNBC tumors evade immune surveillance. Many tumor cells co-opt innate and adaptive immune system mechanisms through direct upregulation of PD-L1 or through recruitment of immune suppressive cells. These forms of immune evasion are in play for tumors with high gene mutation burdens, such as select TNBC subtypes. In the current period, we discovered that some TNBC tumors with high mutation loads remain “immune cold” due to absence of immune cells in the tumor and enrichment of immune suppressive cells in the microenvironment. Immunotherapies targeting the PD-1/PD-L1 pathway continue to be a paradigm shift in the treatment of metastatic cancers with high mutation rates, thus it is critical to understand how to align appropriate TNBC patients with this therapeutic advance. As combination chemo-immunotherapy advances toward FDA approval for metastatic TNBC, it further catalyzes the need to understand how specific chemotherapeutic agents can enhance TNBC subtype-specific response to anti-PD-1/PD-L1 therapy in order to determine the most efficacious combinations. The mechanisms by which chemotherapy modulates neoantigen burden, T-cell function, and immune-suppressive cell function in TNBC are largely unknown. We propose to test the interrelated hypotheses that: (1) standard chemotherapies modulate tumor immune response targeted by anti-PD-L1 therapy in a TNBC-subtype specific manner; and (2) subtype-specific TNBC preclinical models will provide insights to chemotherapy-specific systemic and tumor microenvironment mechanisms of immune suppression. The project's Specific Aims are: Aim 1: To determine mechanisms by which standard chemotherapies modulate tumor immune response in combination with checkpoint immunotherapy; Aim 2: To determine mechanisms by which by tumor secreted proteins and exosomes modulate the immune system in metastatic TNBC subtypes; and Aim 3: To evaluate the feasibility of targeting the tumor microenvironment myeloid-derived cells. IMPACT: Our overall goal is improved outcomes for TNBC patients through alignment of combination therapy directed by knowledge of TNBC subtypes and immunomodulatory features. Through the comprehensive analysis of biospecimens, our established multi- disciplinary team will develop biomarkers for PD-L1 response and define the effects of chemotherapy on distinct immune cell populations. The discovery of new immune-evasion mechanisms will lead to actionable molecular targets for future drug discovery efforts impacting metastatic TNBC and other breast cancers.