ABSTRACT

Breast cancer is the most common malignant tumor in women. Its incidence is associated with obesity and metabolic syndrome (MetS), which are highly prevalent world widely and have been identified as poorer prognosis factors in breast cancer including triple-negative breast cancer (TNBC), which has poorer response to chemotherapy, radiotherapy, and endocrine therapy. Programmed death ligand 1 (PD-L1) is one of the immune checkpoints ligands that facilitates tumor escape and progress. Obesity/MetS could cause systemic inflammation and immune disorders, however, whether and how obesity/MetS affect PD-L1 expression in breast cancer had not been clarified. In the present study, we examined the PD-L1 expression profile in breast cancer either in online database or cell lines. We found higher PD-L1 mRNA level but not DNA copy number in breast cancer than normal breast tissue, and higher PD-L1 expression in TNBC than other subtypes. Moreover, we found a positive relationship between PD-L1 expression in TNBC and metabolic complications in patients. Next, obesity/MetS related M1 macrophage was found to promote the expression of PD-L1 in breast cancer cells cocultured with polarized macrophages derived from either monocyte-like cell line THP-1 or Wistar rat models. IL6/JAK/STAT pathway was further identified to be involved in the process. In addition, we discovered that the PD-L1 expression promoted by obesity/MetS could be restored by telmisartan, one of the angiotensin II receptor blockers (ARBs) and could affect macrophage polarization, through its selective peroxisome proliferator-activated receptor-gamma (PPARG) activation and NFKB p65 inhibition and therefore downregulates IL6 secretion from M1 macrophage.

摘要

乳腺癌是女性最常见的恶性肿瘤。其发病率与肥胖和代谢综合征 (MetS) 相关，它们在世界范围内高度流行，已被确定为乳腺癌预后较差的因素，包括三阴性乳腺癌 (TNBC)，其对化疗、放疗和治疗的反应较差。内分泌治疗。程序性死亡配体 1 (PD-L1) 是促进肿瘤逃逸和进展的免疫检查点配体之一。肥胖/MetS 可能导致全身炎症和免疫紊乱，然而，肥胖/MetS 是否以及如何影响乳腺癌中 PD-L1 的表达尚未阐明。在本研究中，我们检查了在线数据库或细胞系中乳腺癌中的 PD-L1 表达谱。我们发现乳腺癌中的 PD-L1 mRNA 水平高于正常乳腺组织，但 DNA 拷贝数没有，TNBC 中的 PD-L1 表达高于其他亚型。此外，我们发现 TNBC 中 PD-L1 表达与患者代谢并发症之间存在正相关关系。接下来，发现肥胖/MetS 相关的 M1 巨噬细胞可促进 PD-L1 在与来自单核细胞样细胞系 THP-1 或 Wistar 大鼠模型的极化巨噬细胞共培养的乳腺癌细胞中的表达。IL6/JAK/STAT 通路被进一步确定参与该过程。此外，我们发现替米沙坦（一种血管紧张素 II 受体阻滞剂（ARB））可以恢复肥胖/MetS 促进的 PD-L1 表达，并可能影响巨噬细胞极化，