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.

抽象的。非洲妇女（AA）的美国妇女的乳腺癌率不断上升和差距 AAS与欧洲血统（EA）妇女之间的死亡率仍然存在，其原因很大程度上是 未知。调查了以下假设，即非洲内在传染病的进化适应 例如疟疾，导致了更强大的免疫调查，但可能更具侵略性的乳腺癌 随着预后较差，我们发现免疫途径中SNP分布的祖先差异引人注目， 以及循环的细胞因子和全身免疫响应。将我们的研究扩展到本地免疫响应 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 来自AAS的乳腺肿瘤比EAS中的乳腺肿瘤。因为TIL通常与更好的生存有关，但是AA有 在一项试点研究中，较差的预后，我们调查了肿瘤组织中各种免疫细胞亚型是否不同 EAS和AAS。我们发现TIL组成的基因表达谱和平衡的重要转变 免疫反应，包括耗尽的CD8与AAS中的总CD8 T细胞的更高比例，这是 生存分析中的独立预后因素。这些初步发现使我们假设 AAS中免疫反应的强大性质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性或难治性的恶性表型。解决 我们的假设，我们将采用多方面的方法，建立在既定的妇女健康圈子上 研究（WCHS）以恢复EA病例的入学并继续招募AAS，以便我们有足够的 比较和研究来自AA和EA女性肿瘤的免疫特征的统计能力。我们将首先 在250个AA中与250名EA患者相比 使用Vectra多重免疫荧光测定法对顶部标记和空间表征的验证 来自1,500 AA与716名EA患者的肿瘤，考虑到其他分子特征不同的肿瘤 两组之间。我们将检查免疫表型与乳腺癌生存之间的关系，因为 以及与炎症相关的流行病学和社会因素可能在EAS和AAS之间有所不同，或者是 与ER状态相关的风险差异相关，以调查为什么乳腺肿瘤免疫响应会有所不同 通过种族。为了完成这项研究，我们将使用全面的表型和功能测定 确定来自AA与EA癌症患者的固有反应相对于健康对照。 我们的研究将在免疫标志物和功能水平上提供证据，表明来自AA的乳腺肿瘤 妇女的免疫细胞曲目更强，但其TME的平衡转向不利 功能失调状态。我们的发现可能会为关注乳腺癌的免疫疗法的临床研究提供信息 在AA妇女中，可以指导免疫疗法激活疲惫的T细胞的道路，以确保所有人 一组患者将从癌症免疫疗法中获得同等的好处。