The Role of Tumor-Infiltrating Immune Cells and Estrogen Receptor Expression in Racial Disparities in Breast Cancer Biology.

摘要：非裔美国人(AA)女性更容易患上侵袭性肿瘤，存活率也更低 而不是欧洲裔美国女性。理解这种差异背后的生物学机制是一个 对公共卫生有重大影响的严重未得到满足的需求。肿瘤免疫环境可能在 乳腺癌差异，特别是在肿瘤发生和发展中起作用的肿瘤浸润性淋巴细胞(TIL) 疾病的发展。使用来自大型流行病学病例对照研究的H&E染色的玻片，我们有 研究发现，AA女性的TIL水平明显高于EA女性--特别是在雌激素方面 受体(ER)阴性亚群。这表明肿瘤免疫反应存在明显的生物学差异。 与种族和ER状态相关，也提出了一个难题，在这个难题中，TIL通常与 AA女性的预后更好，她们患乳腺癌的情况通常更糟。这些发现表明 免疫细胞群体的特定组成及其在肿瘤内的空间排列 环境可能是TIL在乳腺癌进展中作用的重要缓解因素，以及 AA和EA女性肿瘤的差异。我们的纳米线泛癌免疫的初步数据 专家小组支持这一观点，揭示再生障碍性贫血女性的基因表达签名表明 与电针女性相比，耗尽的T细胞水平，即破坏肿瘤细胞的能力减弱， 与观察到的AA女性较差的存活率一致。在这里，免疫基因表达谱也不同 通过ER状态，指出ER在乳腺癌中的潜在免疫调节作用。 到目前为止，大多数检查TIL的研究都是在以EA女性为主的队列中进行的，而且是深入的 在大量AA女性队列中缺乏免疫档案研究。为了解决这一缺陷，我们将 使用Vectra®定量病理系统的多光谱染色和成像来描绘 妇女健康圈996例乳腺癌免疫细胞群和ER表达的研究 学习。基于我们的初步数据，我们建议评估两个免疫荧光小组，每个小组都有 多个生物标志物的空间形态背景。虽然两个小组都将包括急诊室和 区分细胞角蛋白标记物，第1组将包括四个常见的T细胞标记物(CD3、CD4、CD8、FOXP3)， 小组2将包括T细胞耗竭的标志物(TIGIT、LAG3、PD-1)，这些标记物可能在 AA和EA女性之间的差异免疫反应。我们的建议涉及全面实施一项 新一代生物标志物评估技术--多重染色、多光谱成像、自动化 评分和数字空间分析。乳腺肿瘤免疫状况的全面比较 关于RACE和ER的表达将有助于我们理解免疫逃逸机制，以及如何 这些过程因祖先不同而不同。这将是设计免疫治疗策略的关键，它将同样 使再生障碍性贫血妇女受益，有助于减少乳腺癌的种族差异。

ABSTRACT: African-American (AA) women are more likely to have aggressive tumors and poorer survival than European-American (EA) women. Understanding the biological mechanisms underlying this disparity is a critical unmet need with major public health implications. The tumor immune milieu may play a pivotal role in breast cancer disparities, specifically tumor infiltrating lymphocytes (TILs) that have roles in oncogenesis and disease progression. Using H&E stained slides from a large epidemiological case-control study, we have discovered that AA women have significantly higher levels of TILs than EA women – especially in the estrogen receptor (ER) negative subgroups. This indicates a distinct biological difference in the tumor immune response related to race and ER status, and also presents a conundrum in which TILs that are often associated with better outcome are higher in AA women, who typically fare worse with breast cancer. These findings indicate that the specific composition of immune cell populations and their spatial arrangement within the tumor environment are likely to be important mitigating factors for the role of TILs in breast cancer progression, and tumor differences between AA and EA women. Our preliminary data from the NanoString PanCancer Immune Panel support this idea by revealing that AA women have gene expression signatures indicative of higher levels of exhausted T cells than EA women, which have a diminished capacity to destroy tumor cells, consistent with the poorer survival observed in AA women. Here, immune gene expression profiles also varied by ER status, pointing to a potential immunoregulatory role of ER in breast cancer. To date, most studies that examine TILs do so in cohorts of predominantly EA women and in-depth immune profiling studies in large cohorts of AA women are lacking. To address this shortcoming, we will employ multispectral staining and imaging with the Vectra® Quantitative Pathology System to delineate immune cell populations and ER expression in 996 breast cancer samples from the Women's Circle of Health Study. Building on our preliminary data, we propose to evaluate two immunofluorescence panels, each with multiple biomarkers in their spatio-morphological context. While both panels will include ER and a differentiating cytokeratin marker, panel 1 will include four common T cell markers (CD3, CD4, CD8, FOXP3), and panel 2 will include markers of T cell exhaustion (TIGIT, LAG3, PD-1) that may play a key role in the differential immune response between AA and EA women. Our proposal involves the full implementation of a new generation of biomarker assessment techniques – multiplexed staining, multispectral imaging, automated scoring, and digital spatial analyses. A thorough comparison of the immune landscape in breast tumors in regards to race and ER expression will inform our understanding of immune escape mechanisms, and how these processes differ by ancestry. This will be critical for designing immunotherapy strategies that will equally benefit AA women, serving to reduce racial disparities in breast cancer.