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

三阴性乳腺癌(TNBC)占乳腺癌发病的15%-20%。这种癌症的标准治疗方法是化疗。然而，TNBC的侵袭性行为往往会导致化疗耐药和高转移性复发率。Periostin(POSTN)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。我们最近发现，在胰腺神经内分泌肿瘤中，POSTN通过巨噬细胞募集来介导抗血管生成治疗的抵抗。值得注意的是，它的缺失抑制了单核/巨噬细胞的募集，并增强了细胞毒性CD8+T细胞的渗透。一项最新发现表明，肿瘤相关巨噬细胞通过支持PD1+调节性T细胞而参与免疫检查点阻断(ICB)抵抗，后者隔离PD1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，因为它能够触发间质POSTN的产生，导致亲肿瘤的巨噬细胞的招募，从而促进肿瘤的生长。在这项工作的基础上，我们将研究POSTN介导的巨噬细胞免疫及其对T细胞免疫的影响。在这里，我展示了化疗诱导同基因小鼠模型TNBC原发肿瘤中POSTN的产生，并且它特别沉积在侵袭性前沿。此外，在2D实验中，当人类癌细胞和成纤维细胞直接接触时，化疗会增加POSTN的表达。我目前正在优化两个3D模型：原代TNBC的半高通量脱细胞组织模型和胶原凝胶中的三培养，以从功能和力学上表征化疗/ICB治疗期间POSTN的调节，并研究促炎单核细胞的极化和募集。总体而言，了解TNBC中化疗耐药的性质对未来治疗这种侵袭性癌症的治疗方法的开发是有益的。

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.