The Tumor Microenvironment and Lymphatic Remodeling in Postpartum Breast Cancer

总结/摘要： 从长远来看，怀孕降低了乳腺癌（BC）的风险，但与BC增加有关， 产后乳腺癌（PPBC）在分娩后至少十年。PPBC通常对两者都更具侵略性 与非PPBC相比，晚期和死亡风险更高。目前唯一可以提供的信息是 减少PPBC的可能方法是基于母乳喂养，最近，非母乳喂养的可能作用 甾体抗炎药（NSAID）。除了关于如何修改PPBC风险的稀疏数据外， PPBC诊断后与风险分层相关的信息，以改善常规基因组治疗的结局 签名和临床标志物不适合诊断为BC的年轻女性。我们的目标是解决这些主要问题， 通过检查肿瘤内PPBC环境来确定间隙。研究表明淋巴管的扩张 血管，炎症和产后重塑期间免疫抑制的增加特征， 乳腺在没有母乳喂养或过早停止母乳喂养的情况下会恶化， 环境更有利于肿瘤生长。这种放任直接导致了 肿瘤侵袭和转移与年轻女性BC死亡率的上升有关。肿瘤浸润 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， 代表肿瘤微环境（TME）的可测量病理特征。有前景的数据 提示脑信号蛋白7A（SEMA 7A）、CD 68和Podoplanin（PDPN）的富集与低表达相关。 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 淋巴管生成和免疫抑制，通过SEMA 7A、CD 68、PDPN和PD-L1/PD-1测量 表达通过多光谱定量免疫荧光，在一个年轻女性的BC病例队列， 152例PPBC病例（诊断时间<5年）与272例非PPBC病例（诊断时间≥10年）匹配 从分娩开始）在诊断时的年龄。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和联合关联 脉管系统我们将独立检查每种表型，并一起开发TME多表型 成绩.我们的目的是检查功能特异性TME表型和 开发的TME多表型评分（1）PPBC状态和（2）总生存期。我们也（3）检查 诊断前生活方式行为（即，母乳喂养、NSAID摄入、体力活动） 以及TME表型和评分。没有基因组特征或临床标志物可以指导治疗 也不能预测年轻女性的乳腺癌因此，对于青年妇女的业务连续性总体而言，以及具体而言， 需要定义预测性生物标志物，并提供对可改变的生物学功能的深入了解。 行为。据我们所知，这是第一项通过密度和空间来研究TME特征的研究。 病理学为年轻女性的BC和第一个暂时检查生活方式行为和乳房TME。

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.