The Tumor Microenvironment and Lymphatic Remodeling in Postpartum Breast Cancer

摘要/摘要： 从长远来看，怀孕会降低乳腺癌(BC)的风险，但与BC的增加有关，这种增加被称为 产后乳腺癌(PPBC)在分娩后至少十年。PPBC通常对这两种情况都更具侵略性 与非PPBC相比，晚期和更高的死亡风险。目前唯一可供告知的信息 降低PPBC的可能方法是基于母乳喂养，最近，非母乳喂养可能起到的作用 类固醇抗炎药(NSAIDs)。除了关于如何修改PPBC风险的稀少数据外，更少的是 与PPBC诊断后风险分层相关的信息，以改善常规基因组学结果 签名和临床标记物不适合被诊断为BC的年轻女性。我们的目标是解决这些主要问题 通过检查PPBC的肿瘤内环境来发现差距。研究表明淋巴管的扩张 产后重塑期间的血管系统、炎症和免疫抑制增加的特征 如果没有或提前停止母乳喂养，乳腺会恶化，从而使 环境对肿瘤的生长更为宽容。这种放任直接导致了 肿瘤的侵袭和转移与年轻女性BC死亡率的上升有关。肿瘤浸润性 免疫细胞通过它们的类型、功能以及与肿瘤和其他间质成分的相互作用，提供 代表肿瘤微环境(TME)的可测量的病理特征。前景看好的数据 提示信号素7A(SEMA7A)、CD68和泊多拉宁(PDPN)的丰富与不良相关 BC预后，机制尚不清楚。因此，我们将描述巨噬细胞介导的TME的特征 用SEMA7A、CD68、PDPN和PD-L1/PD-1检测淋巴管生成和免疫抑制 通过多光谱定量免疫荧光在1例年轻女性BC病例中的表达 152例PBC患者(出生后5年确诊)与272例非PPBC患者(诊断为≥10年)相匹配 从分娩开始)确诊时的年龄。我们将通过测量功能特定的TME表型 蛋白质丰度与肿瘤和淋巴管的空间邻近程度之间的独立和联合关系 脉管系统。我们将单独和共同检查每种表型，以开发TME多表型 得分。我们的目标是研究功能特异的TME表型和TME表型之间的独立关联 建立的TME多表型评分与(1)PPBC状态和(2)总生存期有关。我们还(3)检查 诊断前生活方式行为(如母乳喂养、非甾体抗炎药摄入量、体力活动)之间的关系 以及TME表型和评分。没有基因组签名或临床标记来告知治疗学 也不是年轻女性BC的预后。因此，对于年轻女性的BC总体和PPBC来说，战略是 需要定义预测性生物标志物，并提供对可修改的功能生物学的洞察 行为。据我们所知，这是第一次从密度和空间上考察TME特征的研究 为年轻女性的BC和第一个临时性检查生活方式行为和乳房TME的病理学。

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.