Investigating the role of Periostin in chemotherapy resistance via macrophage recruitment in TNBC

三阴性乳腺癌（TNBC）占乳腺癌发病率的15-20%。这类癌症的标准治疗是化疗。然而，TNBC的侵袭性行为通常导致化疗耐药性以及高转移复发率。骨膜蛋白（Periostin，POS 2）是一种细胞外基质蛋白，在乳腺癌中高表达，与预后不良相关.我们最近的研究表明，在胰腺神经内分泌肿瘤中，通过巨噬细胞的募集，POR 4介导了抗血管生成治疗的抵抗。值得注意的是，其缺失抑制单核细胞/巨噬细胞募集并增强细胞毒性CD 8 + T细胞浸润。最近的一项发现表明，肿瘤相关巨噬细胞通过支持PD 1+调节性T细胞参与免疫检查点阻断（ICB）抗性，后者可隔离PD 1抗体。因此，这些发现可能支持我们的假设，即化疗可能无法在TNBC中产生切实的反应，因为它能够触发基质过氧化物酶产生，导致促肿瘤巨噬细胞的募集，这反过来又促进肿瘤生长。在这项工作的基础上，我们将研究POSTN介导的巨噬细胞免疫和对T细胞免疫的影响。在这里，我表明，化疗诱导POR 4生产的TNBC同基因小鼠模型的原发性肿瘤，它是特别沉积在侵入性的前沿。此外，在2D中，当人类癌细胞和成纤维细胞直接接触时，化疗增加了POR 4的表达。我目前正在优化两个3D模型：原发性TNBC的半高通量去细胞化组织模型和胶原凝胶中的三种培养物，以在化学疗法/ICB治疗期间功能和机械地表征POL 4调节，并研究促炎性单核细胞的极化和募集。总的来说，了解TNBC中化疗耐药性的性质可能有助于未来开发治疗这种侵袭性癌症的疗法。

Triple negative breast cancer (TNBC) accounts for 15-20% of incident breast cancers. The standard-of-care for this type of cancer is chemotherapy. However, the aggressive behaviour of TNBC often leads to chemotherapy resistance as well as a high rate of metastatic relapses. Periostin (POSTN) is an extracellular matrix protein, highly expressed in breast cancer and correlates with poor prognosis. We have recently shown that POSTN mediates resistance to anti-angiogenic therapy via macrophage recruitment in pancreatic neuroendocrine tumours. Notably, its deletion dampens monocyte/macrophage recruitment and enhances cytotoxic CD8+ T-cell infiltration. A most recent finding reveals that tumour-associated macrophages are implicated in immune-checkpoint blockade (ICB) resistance by supporting PD1+ regulatory T cells, which sequester the PD1 antibody. These findings may thus support our hypothesis that chemotherapy may fail to produce tangible responses in TNBC because of its ability to trigger stromal POSTN production, leading to the recruitment of pro-tumoural macrophages, which in turn facilitate tumour growth. Building on this work we will investigate POSTN-mediated macrophage immunity and the resulting effect on T-cell immunity. Here, I show that chemotherapy induces POSTN production in primary tumours of syngeneic mouse models of TNBC and it is particularly deposited at the invasive front. Moreover, in 2D, chemotherapy increases POSTN expression when human cancer cells and fibroblast are in direct contact. I am currently optimising two 3D models: a semi-high throughput decellularised tissue model of primary TNBC, and tri-culture in collagen gels, to functionally and mechanistically characterize POSTN regulation during chemotherapy/ICB therapy, and study polarization and recruitment of pro-inflammatory monocytes. Overall, understanding the nature of chemotherapy resistance in TNBC can be beneficial in the future for the development of therapies to treat this aggressive type of cancer.