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

抽象的。美国非洲裔(AA)女性的乳腺癌发病率继续上升， AAS和欧洲血统(EA)妇女之间的死亡率仍然存在，其原因主要是 未知。研究对非洲地方性传染病的进化适应的假设， 如疟疾，导致更强大的免疫反应，但可能更具侵袭性的乳腺癌 在预后较差的情况下，我们发现SNP在免疫途径中的分布存在显著的祖先差异， 循环中的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，我们发现肿瘤浸润性淋巴细胞(TIL)在 来自AAS的乳腺肿瘤多于来自EAS的乳腺肿瘤。因为TIL通常与更好的存活率相关，但美国癌症协会 在一项初步研究中，我们调查了肿瘤组织中不同免疫细胞亚型在 EAS和AAS。我们发现TIL组成和平衡的基因表达谱发生了重要的变化 免疫反应，包括AAS中耗尽的CD8/总CD8 T细胞的较高比率，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假设 AAS中强大的免疫反应对于重塑乳腺肿瘤的生物学很重要， 最终导致出现更具免疫抵抗力或难治性的恶性表型。致信地址 我们的假设是，我们将采取多管齐下的方法，建立在既定的妇女健康圈基础上 研究(WCHS)恢复招收EA个案，并继续招聘AA，以便我们有足够的资金 比较和研究AA和EA女性肿瘤免疫状况的统计能力。我们将首先 在250名AA和250名EA患者中，使用转录剪裁分析来描述和比较乳房TME，接下来是 用Vectra多重免疫荧光分析验证TOP标记和空间特征 来自1500名AA患者和716名EA患者的肿瘤，考虑到其他不同的分子特征 在小组之间。我们将研究免疫表型和乳腺癌存活率之间的关系， 以及与炎症相关的流行病学和社会因素，这些因素在EAs和AAs之间可能不同，或者是 通过ER状态与风险的不同关联，以调查为什么乳腺肿瘤的免疫反应会不同 按种族划分。为了补充这项研究，我们将使用全面的表型和功能分析来 确定AA和EA癌症患者的免疫细胞相对于健康对照的固有反应。 我们的研究将在免疫标记物和功能水平上提供证据，证明再生障碍性贫血引起的乳腺肿瘤 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移 功能失调状态。我们的发现可能为乳腺癌免疫治疗的临床研究提供参考。 在AA妇女中，并可能指导免疫疗法激活耗尽的T细胞，确保所有 患者群体将从癌症免疫治疗中获得平等的好处。

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.