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.
在实体瘤中，阻断CD47-SIRPα相互作用产生的“别吃我”信号虽能产生显著的抗肿瘤效应，但其效果相较于在血液系统恶性肿瘤中的疗效仍显有限。激活巨噬细胞抗肿瘤活性不仅需要抑制“别吃我”信号，同时还需激活“吃我”（前吞噬细胞）信号。值得注意的是，细胞毒性T淋巴细胞相关抗原4（CTLA4）抗体已被证实能在肿瘤微环境中刺激Fc受体介导的活性吞噬细胞，从而产生“吃我”信号。本研究提出，同时靶向CD47和CTLA4可通过阻断“别吃我”信号并触发“吃我”信号，从而增强抗肿瘤效果。实验数据证实，在LLC细胞移植的荷瘤小鼠中，联合靶向CD47与CTLA4能增强对实体瘤的免疫应答。该效应通过减少髓源性抑制细胞浸润，同时增加效应记忆CD8+T细胞、NK1.1+CD8+T细胞及活化自然杀伤T细胞的数量实现。此外，联合治疗还能缓解贫血症状。机制研究表明，抗CD47抗体可通过调控Foxp1上调非小细胞肺癌细胞中CTLA4的表达水平。同时，靶向CD47能通过促进CD4+T细胞浸润来推动肿瘤血管正常化。这些发现表明，CD47与CTLA4的双重靶向治疗通过协同调控“吃我”与“别吃我”信号、重塑免疫微环境及促进肿瘤血管正常化发挥抗肿瘤作用。该联合治疗方案为实体瘤的有效治疗提供了新策略。
肿瘤(癌症)患者之家