Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry

抽象的。非洲裔美国女性 (AA) 的乳腺癌发病率持续上升，且男女之间的差距 AA 和欧洲血统女性 (EA) 之间的死亡率持续存在，其原因主要是 未知。研究非洲地方性传染病的进化适应这一假设， 例如疟疾，会导致更强大的免疫反应，但可能会导致更具侵袭性的乳腺癌 由于预后较差，我们发现免疫通路中 SNP 的分布存在显着的祖先差异， 以及循环细胞因子和全身免疫反应。将我们的研究扩展到局部免疫反应 在肿瘤微环境（TME）中，我们发现肿瘤浸润淋巴细胞（TIL）的存在更强 AA 中的乳腺肿瘤多于 EA 中的乳腺肿瘤。因为 TIL 通常与更好的生存相关，但 AA 预后较差，在一项试点研究中，我们研究了肿瘤组织中的各种免疫细胞亚型是否存在差异 EA 和 AA。我们发现 TIL 组成和平衡的基因表达谱发生了重要转变 免疫反应，包括 AA 中耗尽的 CD8 与总 CD8 T 细胞的比例较高，这是一种 生存分析中的独立预后因素。这些初步发现使我们推测 AA 中免疫反应的强大性质对于重塑乳腺肿瘤的生物学非常重要， 最终导致出现更具免疫抵抗性或难治性的恶性表型。致地址 根据我们的假设，我们将在已建立的女性健康圈的基础上采取多管齐下的方法 研究（WCHS）恢复 EA 案例的招募并继续招募 AA，以便我们有足够的资源 比较和研究 AA 和 EA 女性肿瘤免疫特征的统计能力。我们首先会 使用转录组分析对 250 名 AA 患者和 250 名 EA 患者进行乳腺 TME 分析和比较，然后 使用 Vectra 多重免疫荧光测定验证顶级标记和空间表征 1,500 名 AA 患者与 716 名 EA 患者的肿瘤，并考虑到其他不同的分子特征 组之间。我们将研究免疫表型与乳腺癌生存之间的关系，如 以及与炎症相关的流行病学和社会因素，这些因素在 EA 和 AA 之间可能有所不同，或者是 与 ER 状态的风险存在差异相关，以调查为什么乳腺肿瘤免疫反应会有所不同 通过种族。为了补充这项研究，我们将采用全面的表型和功能测定来 确定 AA 与 EA 癌症患者相对于健康对照的免疫细胞的固有反应。 我们的研究将在免疫标记物和功能水平上提供证据表明乳腺肿瘤来自 AA 女性拥有更强的免疫细胞库，但她们的 TME 平衡向不利的方向转变 功能失调状态。我们的研究结果可能为针对乳腺癌的免疫疗法的临床研究提供信息 在 AA 女性中，可能会指导免疫疗法激活耗尽的 T 细胞，确保所有 不同群体的患者将从癌症免疫治疗中获得同等的益处。

Abstract. Breast cancer rates in American women of African ancestry (AA) continue to rise and the gap in mortality between AAs and women of European ancestry (EA) persists, the reasons for which are largely unknown. Investigating the hypothesis that evolutionary adaptation to endemic infectious diseases in Africa, such as malaria, resulted in more robust immune responses, but potentially more aggressive breast cancers with poorer prognoses, we found striking ancestral differences in distributions of SNPs in immune pathways, and in circulating cytokines and systemic immune response. Extending our research to local immune response in the tumor microenvironment (TME), we found a stronger presence of tumor infiltrating lymphocytes (TILs) in breast tumors from AAs than in EAs. Because TILs are typically associated with better survival, but AAs have poorer prognosis, in a pilot study, we investigated if various immune cell subtypes in tumor tissues differed in EAs and AAs. We found an important shift in gene expression profiles for TIL composition and the balance of immune responses, including a higher ratio of exhausted CD8 to total CD8 T cells in AAs, which was an independent prognostic factor in survival analysis. These preliminary findings have led us to hypothesize that the robust nature of the immune response in AAs is important for reshaping the biology of breast tumors, ultimately leading to the emergence of a more immune-resistant or refractory malignant phenotype. To address our hypotheses, we will take a multi-pronged approach built upon the established Women’s Circle of Health Study (WCHS) to resume enrollment of EA cases and continue recruitment of AAs, so that we will have ample statistical power to compare and investigate immune profiles in tumors from AA and EA women. We will first profile and compare breast TMEs using transcriptomic profiling in 250 AA vs. 250 EA patients, followed by validation of top markers and spatial characterization using Vectra multiplex immunofluorescence assay in tumors from 1,500 AA vs. 716 EA patients, with consideration of other molecular characteristics that differ between groups. We will examine relationships between immune phenotypes and breast cancer survival, as well as inflammation-related epidemiologic and social factors that may vary between EAs and AAs, or are differentially associated with risk by ER status, to investigate why breast tumor immune response would differ by race. To complement this research, we will employ comprehensive phenotypic and functional assays to determine the inherent response of immune cells from AA vs. EA cancer patients relative to healthy controls. Our study will provide evidence at both immune marker and functional levels that breast tumors from AA women have a stronger immune cell repertoire, but the balance of their TME is shifted towards an unfavorable dysfunctional state. Our findings may inform clinical investigations of immunotherapy focusing on breast cancer in AA women, and may guide the way for immunotherapy to activate exhausted T cells, ensuring that all groups of patients will receive equal benefits from cancer immunotherapy.