The Tumor Microenvironment and Lymphatic Remodeling in Postpartum Breast Cancer

产后乳腺癌的肿瘤微环境和淋巴重塑

基本信息

批准号：
10522393
负责人：
Jasmine Alise McDonald
金额：
$ 56.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522393
关键词：
Address Age Animals Anti-Inflammatory Agents Aspirin Behavior Biological Process Biology Black race Breast Cancer Risk Factor Breast Cancer Treatment Breast Feeding Cancer Prognosis Catalogs Cells Childbirth Clinical Clinical Markers Data Diagnosis Disease Elements Environment Evidence based treatment Goals Immunofluorescence Immunologic Immunohistochemistry Immunomodulators Immunosuppression Incidence Inflammation Intake Joints Life Style Link Liver Lymphangiogenesis Lymphatic Mammary Neoplasms Mammary gland Measurable Measures Mediating Modeling Molecular Profiling Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Not Hispanic or Latino Nulliparity Outcome PD-1/PD-L1 Pathologic Pathologic Processes Pathology Pathway interactions Patient Rights Phenotype Physical activity Physical shape Postpartum Period Predisposition Pregnancy Prevention strategy Prognosis Proteins Risk Risk Factors Role Sampling Semaphorins Therapeutic Tissues Triad Acrylic Resin Tumor Biology Tumor Cell Invasion Tumor-infiltrating immune cells Woman aged anti-PD1 therapy base behavioral phenotyping breast cancer family registry cancer recurrence carcinogenesis caregiving cohort density genomic signature high risk human data immunoregulation improved improved outcome insight lymphatic vasculature lymphatic vessel macrophage malignant breast neoplasm modifiable behavior modifiable risk mortality mortality risk mouse model parous permissiveness podoplanin postpartum breast cancer pre-clinical predictive marker prognostic public health priorities risk stratification targeted treatment trend tumor tumor growth tumor microenvironment tumor progression young woman

项目摘要

SUMMARY/ABSTRACT: Pregnancy reduces breast cancer (BC) risk in the long-run but is associated with increased BC known as postpartum breast cancer (PPBC) for at least a decade after delivery. PPBC is often more aggressive with both late stage and higher risk of death compared to non-PPBC. Currently the only available information to inform women of possible ways to reduce PPBC is based on breastfeeding and more recently, a possible role for non- steroidal anti-inflammatories (NSAIDs). In addition to sparse data on how to modify PPBC risk, there is even less information related to risk stratification after PPBC diagnosis to improve outcomes with routine genomic signatures and clinical markers not suited for young women diagnosed with BC. We aim to address these major gaps by examining the intratumoral PPBC environment. Studies suggest that the expansion of the lymphatic vasculature, inflammation, and increased features of immune suppression during postpartum remodeling of the mammary gland is exacerbated in the absence- or early-cessation- of breastfeeding which makes the environment more permissive to tumor growth. This permissiveness contributes directly to the increased risk of tumor invasion and metastasis linked to the rising rates of BC mortality in young women. The tumor infiltrating immune cells, through their type, function, and interactions with the tumor and other stromal elements, provide a measurable pathological signature representative of the tumor microenvironment (TME). Promising data suggests that enrichment for Semaphorin 7A (SEMA7A), CD68, and Podoplanin (PDPN) is associated with poor BC prognosis, with mechanisms unclear. Therefore, we will profile the TME for features of macrophage mediated lymphangiogenesis and immune suppression, as measured by SEMA7A, CD68, PDPN, and PD-L1/PD-1 expression via multispectral quantitative immunofluorescence, in a young women’s BC case-cohort of 152 PPBC cases (diagnosed <5 years from childbirth) matched to 272 non-PPBC cases (diagnosed ≥10 years from childbirth) on age at diagnosis. We will measure functional-specific TME phenotypes by measuring the independent and joint associations between protein abundance and spatial proximity to tumor and the lymphatic vasculature. We will examine each phenotype independently and together to develop TME poly-phenotype scores. We aim to examine the independent association between the functional-specific TME phenotypes and the developed TME poly-phenotype score with (1) PPBC status and (2) overall survival. We also (3) examine the association between prediagnostic lifestyle behaviors (i.e., breastfeeding, NSAID intake, physical activity) and TME phenotypes and scores. There are no genomic signatures or clinical markers that inform therapeutics nor prognosis for young women’s BC. Thus, for young women’s BC overall and PPBC specifically, strategies are needed that define predictive biomarkers and provides insight into the functional biology of modifiable behaviors. To our knowledge, this is the first study to examine TME features through density and spatial pathology for young women’s BC and the first to temporally examine lifestyle behaviors and the breast TME.

摘要/摘要：从长远来看，怀孕会降低乳腺癌 (BC) 风险，但与 BC 增加有关，即产后乳腺癌 (PPBC) 在分娩后至少十年内通常更具侵袭性。与非 PPBC 相比，晚期和更高的死亡风险是目前唯一可用的信息。女性减少 PPBC 的可能方法是基于母乳喂养，最近，非哺乳期妇女可能发挥的作用除了类固醇抗炎药 (NSAID) 之外，关于如何降低 PPBC 风险的数据更少。与 PPBC 诊断后风险分层相关的信息，以改善常规基因组结果不适合诊断患有 BC 的年轻女性的特征和临床标志物我们的目标是解决这些主要问题。通过检查瘤内 PPBC 环境的间隙，研究表明淋巴管的扩张。产后血管重塑过程中的脉管系统、炎症和免疫抑制特征的增加如果缺乏母乳喂养或过早停止母乳喂养，乳腺就会恶化，这使得环境对肿瘤的生长更加宽容，这种宽容直接导致了肿瘤风险的增加。肿瘤浸润和转移与年轻女性乳腺癌死亡率上升有关。免疫细胞通过其类型、功能以及与肿瘤和其他基质成分的相互作用，提供代表肿瘤微环境（TME）的可测量病理特征。表明信号蛋白 7A (SEMA7A)、CD68 和 Podoplanin (PDPN) 的富集与不良相关 BC 预后，机制尚不清楚，因此，我们将分析 TME 的巨噬细胞介导的特征。淋巴管生成和免疫抑制，通过 SEMA7A、CD68、PDPN 和 PD-L1/PD-1 测量在年轻女性 BC 病例队列中通过多光谱定量免疫荧光表达 152 例 PPBC 病例（诊断时间<出生后 5 年）与 272 例非 PPBC 病例（诊断时间≥10 年）相匹配从分娩开始）到诊断时的年龄，我们将通过测量功能特异性 TME 表型。蛋白质丰度与肿瘤和淋巴管的空间接近度之间的独立关联和联合关联我们将独立和共同检查每种表型以开发 TME 多表型。我们的目的是检查功能特异性 TME 表型与 TME 之间的独立关联。我们还检查了 (1) PPBC 状态和 (2) 总体生存率的 TME 多表型评分。诊断前生活方式行为（即母乳喂养、非甾体抗炎药摄入量、体力活动）之间的关联以及 TME 表型和评分没有为治疗提供信息的基因组特征或临床标记。因此，对于年轻女性的 BC 整体和具体的 PPBC，策略是：需要定义预测生物标志物并提供对可修饰的功能生物学的深入了解据我们所知，这是第一个通过密度和空间来检查 TME 特征的研究。年轻女性 BC 的病理学，也是第一个临时检查生活方式行为和乳房 TME 的人。