肿瘤微环境的特点是炎症样和免疫抑制情况。尽管癌症相关成纤维细胞 (CAF) 是包括结肠癌在内的各种实体癌的主要基质细胞类型之一，但 CAF 和免疫细胞之间的相互作用在很大程度上仍然未知。 Pentraxin 3 (PTX3) 对促炎细胞因子有反应，调节免疫和组织重塑，但其在肿瘤进展中的参与似乎与背景相关且尚不清楚。利用开放数据库来检查 PTX3 表达与成纤维细胞特征的关联在结肠癌中。进行功能丧失测定，包括对他莫昔芬诱导的 Ptx3 基因敲除小鼠的研究和抗 PTX3 中和抗体 (WHC-001) 的治疗，以评估 PTX3 在结肠癌进展中的参与及其免疫抑制作用。最后，进行生物信息学分析和体外测定，以揭示下游效应器，并破译 CREB1/CEBPB 轴响应 PTX3 和 PTX3 诱导的 M2 巨噬细胞极化促进的参与。临床上，较高的 PTX3 表达与成纤维细胞和成纤维细胞呈正相关。炎症反应特征并与结肠癌患者的不良生存结果相关。阻断 PTX3 显着减少基质细胞介导的肿瘤发展。在同种异体移植结肠肿瘤中 PTX3 失活后，观察到 M2 巨噬细胞群减少和细胞毒性 CD8 T 细胞群增加。我们进一步发现，环AMP反应元件结合蛋白1（CREB1）的激活介导了PTX3诱导的M2巨噬细胞极化的促进。PTX3通过增加M2样巨噬细胞极化和抑制PTX3来促进基质细胞介导的促肿瘤免疫。 WHC-001 是一种潜在的结肠癌治疗策略。© 2024。作者。

The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear.Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization.Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization.PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.© 2024. The Author(s).