Background: A total of 30–40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors. Methods: We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models. Results: We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor. Conclusions: Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.
背景：约30-40%的弥漫性大B细胞淋巴瘤（DLBCL）患者对标准治疗无应答或出现疾病复发。DLBCL的一线治疗方案为利妥昔单抗联合化疗。该治疗通过化疗诱导肿瘤相关巨噬细胞的募集，使其识别并清除经利妥昔单抗调理的DLBCL细胞。然而，目前对DLBCL肿瘤中巨噬细胞募集及功能调控因素的认识仍不充分。 方法：本研究通过体外实验及动物模型，探讨免疫调节脂质鞘氨醇-1-磷酸（S1P）对DLBCL中巨噬细胞活性的影响。 结果：研究表明，在体外及动物模型中，肿瘤源性S1P可介导单核细胞与巨噬细胞的趋化作用，该效应依赖于S1P受体S1PR1。然而，S1P会抑制M1型巨噬细胞对经CD20单克隆抗体（利妥昔单抗与奥法木单抗）调理的DLBCL肿瘤细胞的吞噬作用，该抑制作用可被S1PR1抑制剂逆转。 结论：本研究证实S1P信号通路可调控DLBCL中巨噬细胞的募集及抗CD20单克隆抗体介导的肿瘤细胞杀伤作用。使用S1PR1抑制剂可增强肿瘤细胞的吞噬清除，有望改善患者预后。
肿瘤(癌症)患者之家