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

肿瘤免疫环境和乳腺癌差异：针对非洲和欧洲血统女性的多学科研究

• 批准号: 10404988
• 负责人: Scott I. Abrams
• 金额: $ 99.3万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404988
• 关键词: Address; Africa; African; African ancestry; American; Anti-Inflammatory Agents; Antibodies; Biological Assay; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Characteristics; Chronic; Clinical Research; Communicable Diseases; Complement; Data Set; Dietary Practices; Enrollment; Ensure; Epidemiologic Factors; Equilibrium; Estrogen Receptor Status; Estrogen receptor negative; Estrogen receptor positive; Etiology; European; Flow Cytometry; Gene Expression; Gene Frequency; Genes; Genetic; Goals; Health; Immune; Immune System Diseases; Immune response; Immunity; Immunofluorescence Immunologic; Immunogenomics; Immunologic Markers; Immunotherapy; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Lead; Malaria; Mammary Neoplasms; Maps; Methods; Molecular; Natural Immunity; Nature; Obesity; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Physical activity; Pilot Projects; Plasma; Population; Prognosis; Prognostic Factor; Property; Race; Refractory; Research; Risk; Risk Factors; Role; Shapes; Survival Analysis; T-Lymphocyte; Testing; Tumor Subtype; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Validation; Variant; Woman; adaptive immunity; aggressive breast cancer; breast cancer survival; cancer health disparity; cancer immunotherapy; cancer therapy; candidate marker; case control; clinical investigation; comorbidity; cytokine; cytotoxic; differential expression; epidemiology study; exhaust; exhaustion; genomic locus; immune resistance; immunoregulation; inflammatory milieu; insight; liquid crystal polymer; mRNA Expression; macrophage; malignant breast neoplasm; malignant phenotype; modifiable risk; monocyte; mortality; multidisciplinary; neoplastic cell; non-genetic; peripheral blood; racial difference; recruit; reproductive; social factors; transcriptome; transcriptomics; tumor; tumor microenvironment

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.

抽象。非洲裔美国妇女（AA）的乳腺癌发病率继续上升， AA和欧洲血统（EA）女性之间的死亡率仍然存在，其原因主要是 未知调查进化适应非洲地方性传染病的假设， 例如疟疾，导致更强大的免疫反应，但可能更具有侵略性的乳腺癌， 对于较差的遗传，我们发现免疫途径中SNP分布的祖先差异， 以及循环细胞因子和全身免疫应答。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（TILs）的存在更强， 乳腺癌的发病率高于乳腺癌。因为TIL通常与更好的生存率相关，但AA具有 在一项初步研究中，我们调查了肿瘤组织中的各种免疫细胞亚型是否在 EA和AA。我们发现了一个重要的转变，基因表达谱的TIL组成和平衡， 免疫应答，包括AA中耗尽的CD 8 T细胞与总CD 8 T细胞的比率较高，这是一种免疫应答， 生存分析中独立预后因素。这些初步发现使我们假设， AA中免疫应答的稳健性质对于重塑乳腺肿瘤的生物学是重要的， 最终导致更免疫抗性或难治性恶性表型的出现。解决 我们的假设，我们将采取多管齐下的方法，建立在既定的妇女健康圈 研究（WCHS）恢复招募EA病例并继续招募AA，以便我们有足够的 统计功效来比较和研究AA和EA女性肿瘤中的免疫特征。我们将首先 在250例AA和250例EA患者中使用转录组学分析来分析和比较乳腺TME，然后 使用Vectra多重免疫荧光测定法验证顶级标志物和空间表征， 来自1,500名AA与716名EA患者的肿瘤，考虑到其他分子特征， 在群体之间。我们将研究免疫表型和乳腺癌生存率之间的关系， 以及炎症相关的流行病学和社会因素，这些因素在EA和AA之间可能不同，或者 ER状态与风险差异相关，以研究乳腺肿瘤免疫反应为何不同 种族歧视为了补充这项研究，我们将采用全面的表型和功能测定， 确定来自AA与EA癌症患者的免疫细胞相对于健康对照的固有应答。 我们的研究将在免疫标志物和功能水平上提供证据，表明乳腺肿瘤来自AA 女性有更强的免疫细胞库，但其TME的平衡向不利的方向转移， 功能失调的状态我们的研究结果可能会为乳腺癌免疫治疗的临床研究提供信息 在AA女性中，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疗法中获得同等益处。