Tumor and immune cell co-evolutionary dynamics as a source of racial disparities in breast cancer

摘要 非洲血统的女性（黑人女性）比白色女性更容易患侵袭性乳腺肿瘤 黑人和白色妇女之间的生存差距为40%。肿瘤免疫环境及其对肿瘤免疫的影响 与肿瘤细胞的相互作用可能在解释这种差异方面发挥关键作用。非洲血统与 对免疫激活有更强的反应，黑人女性的乳腺肿瘤对免疫激活有更强的反应， 肿瘤浸润淋巴细胞和CD8 + T细胞高于白色女性。尽管如此，黑人妇女的情况比 患有乳腺癌的白色女性，这与大量的研究表明， 肿瘤浸润性免疫细胞与更好的结果相关。这一明显的矛盾可能会得到调和 Schreiber的免疫编辑模型，其中免疫细胞与肿瘤相互作用以形成肿瘤 免疫原性由于非洲裔女性的免疫反应更强，我们假设， 它们自身的免疫系统通过免疫编辑选择更具侵袭性的乳腺肿瘤。 为了解决这个新的假设，我们将使用冷冻的乳腺肿瘤和血液样本从罗斯韦尔 公园综合癌症中心获得一个单一的数据集，将用于调查两个相关的 研究目的。首先，我们将比较肿瘤内免疫浸润和遗传多样性的空间模式 sample.如果免疫浸润对肿瘤细胞施加选择性压力，则高免疫浸润的空间区域可能是肿瘤细胞的一部分。 浸润应该对应于较低的肿瘤遗传多样性，并且这些区域也预期显示出 免疫编辑的分子特征，表现为新抗原耗竭，抗原呈递突变 基因、免疫抑制或排斥。为了检验这一点，将从乳腺肿瘤中提取组织芯 来自80名患者（40名黑人，40名白色）-一个核心来自高免疫浸润区域，一个来自低免疫浸润区域 浸润将对每个肿瘤核心进行全外显子组测序和RNA-seq，并将序列数据 将使用已建立的生物信息学方法检查遗传多样性和免疫编辑。二是 将比较来自黑人和白色女性的乳腺肿瘤的从RNA-seq数据推断的免疫子集， 免疫编辑的分子特征。我们预计，黑人患者的肿瘤将具有更强的整体 从RNA-seq数据和肿瘤中推断出的免疫反应显示出更多的免疫编辑证据。 我们的建议将采用一套生物信息学技术来比较肿瘤免疫共- 黑人和白色女性乳腺肿瘤的进化景观。我们的研究结果可能会对 这可能为设计有效的联合治疗开辟新的途径 其针对患者的免疫环境和/或祖先背景进行个性化。

ABSTRACT Women of African ancestry (Black women) are more likely to have aggressive breast tumors than White women, and the survival gap between Black and White women is 40%. The tumor immune milieu and its interaction with tumor cells may play a pivotal role in explaining this disparity. African ancestry is associated with a stronger response to immune activation, and breast tumors from Black women have significantly more tumor-infiltrating lymphocytes and CD8+ T cells than White women. Despite this, Black women fare worse than White women with breast cancer, and this at odds with a wealth of studies that show a strong presence of tumor-infiltrating immune cells is correlated with better outcomes. This apparent paradox may be reconciled with Schreiber’s immunoediting model, wherein immune cells interact with the tumor to shape tumor immunogenicity. Because women of African descent have stronger immune responses, we hypothesize that their own immune systems select for more aggressive breast tumors by way of immunoediting. To address this novel hypothesis, we will use frozen breast tumor and blood samples from Roswell Park Comprehensive Cancer Center to obtain a single dataset that will be used to investigate two related research aims. First, we will compare spatial patterns of immune infiltration and genetic diversity within a tumor sample. If immune infiltrates are exerting a selective pressure on tumor cells, spatial regions of high immune infiltration should correspond to lower tumor genetic diversity and these regions are also expected to display molecular signatures of immunoediting, manifested as neoantigen depletion, mutations in antigen presenting genes, immunosuppression, or exclusion. To examine this, tissue cores will be extracted from breast tumors from 80 patients (40 Black, 40 White) – one core from a region of high immune infiltration and one from low infiltration. Whole exome sequencing and RNA-seq will be performed on each tumor core, and sequence data will be examined for genetic diversity and immunoediting using established bioinformatic methods. Second, we will compare breast tumors from Black and White women for immune subsets inferred from RNA-seq data and molecular signatures of immunoediting. We expect that tumors from Black patients will have stronger overall immune responses inferred from RNA-seq data and tumors that show more evidence of immunoediting. Our proposal will employ a suite of bioinformatics techniques to compare the tumor-immune co- evolutionary landscape in breast tumors from Black and White women. Our results may have implications for immunotherapy efficacy by race and may open new avenues for the design of effective combinatory therapies that are personalized for a patient’s immune milieu and/or ancestral background.