在实体瘤中,阻止“不要吃我”信号产生的强大抗肿瘤影响,源于CD47-SIRPα相互作用,受约束,特别是在造血系统恶性肿瘤中的疗效比较。激活巨噬细胞抗肿瘤活性不仅需要抑制“不要吃我”信号,而且还激活了“吃我”(吞噬细胞前)信号。有趣的是,细胞毒性T淋巴细胞相关抗原4(CTLA4)抗体(Ab)已被鉴定为刺激肿瘤微环境中Fc受体介导的活性吞噬细胞,从而产生“吃我”的信号。这项研究假设,同时靶向CD47和CTLA4可以通过同时阻断“不要吃我”信号同时触发“吃我”信号来增强抗肿瘤作用。来自该研究的实验数据证实,CD47和CTLA4的组合靶向增强了LLC细胞移植的荷瘤小鼠中针对实体瘤的免疫力。这种效果是通过减少骨髓来源的抑制细胞浸润,同时增加效应记忆CD8+T细胞的存在来实现的。NK1.1+CD8+T细胞,激活自然杀伤T细胞.同时,联合治疗也减轻了贫血。机械上,显示抗CD47Ab通过调节Foxp1上调NSCLC细胞中的CTLA4水平。此外,靶向CD47被证明通过增加CD4+T细胞的浸润促进肿瘤血管正常化。这些发现表明,CD47和CTLA4的双重靶向通过协调“吃我”和“不要吃我”信号发挥抗肿瘤作用。重塑免疫微环境,促进肿瘤血管正常化。这种联合治疗方法成为有效治疗实体瘤的有效策略。
In solid tumors, the formidable anti-tumor impact resulting from blocking the \"don\'t eat me\" signal, arising from CD47-SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the \"don\'t eat me\" signal, but also the activation of the \"eat me\" (pre-phagocyte) signal. Intriguingly, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody (Ab) has been identified to stimulate Fc receptor-mediated active phagocytes in the tumor microenvironment, thereby generating \"eat me\" signals. This study postulates that concurrently targeting CD47 and CTLA4 could intensify the anti-tumor effects by simultaneously blocking the \"don\'t eat me\" signal while triggering the \"eat me\" signal. The experimental data from this investigation confirm that the combined targeting of CD47 and CTLA4 enhances immunity against solid tumors in LLC cell-transplanted tumor-bearing mice. This effect is achieved by reducing myeloid-derived suppressor cell infiltration while increasing the presence of effector memory CD8+ T cells, NK1.1+ CD8+ T cells, and activated natural killer T cells. Meanwhile, combination therapy also alleviated anemia. Mechanistically, the anti-CD47 Ab is shown to upregulate CTLA4 levels in NSCLC cells by regulating Foxp1. Furthermore, targeting CD47 is demonstrated to promote tumor vascular normalization through the heightened infiltration of CD4+ T cells. These findings suggest that the dual targeting of CD47 and CTLA4 exerts anti-tumor effects by orchestrating the \"eat me\" and \"don\'t eat me\" signals, reshaping the immune microenvironment, and fostering tumor vascular normalization. This combined therapeutic approach emerges as a potent strategy for effectively treating solid tumors.