BioResource Research Center, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Institute of Human Virology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, Guangdong, China.
J Immunother Cancer. 2022 Feb;10(2). doi: 10.1136/jitc-2021-003737.
Chimeric antigen receptor (CAR) T cell therapy has been successfully applied in treating lymphoma malignancies, but not in solid tumors. CD47 is highly expressed on tumor cells and its overexpression is believed to inhibit phagocytosis by macrophages and dendritic cells. Given the antitumor activity against preclinical model of CD47-blocking to induce the innate and adaptive immune system in the tumor microenvironment, here we developed a CAR-T cell secreting CD47 blocker signal regulatory protein α (SIRPα)-Fc fusion protein (Sirf CAR-T) to boost CAR-T cell therapeutic effect in solid tumor therapy.
Murine T cells were transduced to express a conventional anti-Trop2 CAR and Sirf CAR. The expression of SIRPα-Fc fusion protein in the supernatant of CAR-T cells and its effect on macrophage phagocytosis were tested in vitro. In vivo antitumor efficacy of CAR-T cells was evaluated in immunocompetent mice and analysis of the tumor microenvironment in the tumor-bearing mice was performed.
We found that Sirf CAR-T cells dramatically decreased tumor burden and significantly prolonged survival in several syngeneic immunocompetent tumor models. Furthermore, we found that Sirf CAR-T cells induced more central memory T cells (T) and improved the persistence of CAR-T cells in tumor tissue, as well as decreased PD-1 expression on the CAR-T cell surface. In addition, we demonstrated that Sirf CAR-T cells could modulate the tumor microenvironment by decreasing myeloid-derived stem cells as well as increasing CD11c dendritic cells and M1-type macrophages in tumor tissue.
In summary, our findings indicate that CD47 blocker SIRPα-Fc enhances the antitumor efficacy of CAR-T cells and propose to block CD47/SIRPα signaling effect on CAR-T cells function, which could provide a new strategy for successful cancer immunotherapy by rationalizing combination of CD47 blocker and CAR-T cell therapy.
嵌合抗原受体（CAR）T 细胞疗法已成功应用于治疗淋巴瘤恶性肿瘤，但不适用于实体瘤。CD47 在肿瘤细胞上高度表达，其过表达被认为可抑制巨噬细胞和树突状细胞的吞噬作用。鉴于阻断 CD47 可在肿瘤微环境中诱导固有和适应性免疫系统的抗肿瘤活性，我们在此开发了一种分泌 CD47 阻断信号调节蛋白 α（SIRPα）-Fc 融合蛋白的 CAR-T 细胞（Sirf CAR-T），以增强 CAR-T 细胞在实体瘤治疗中的治疗效果。
将鼠 T 细胞转导以表达常规抗 Trop2 CAR 和 Sirf CAR。在体外测试 CAR-T 细胞上清液中 SIRPα-Fc 融合蛋白的表达及其对巨噬细胞吞噬作用的影响。在免疫功能正常的小鼠中评估 CAR-T 细胞的体内抗肿瘤疗效，并对荷瘤小鼠的肿瘤微环境进行分析。
我们发现 Sirf CAR-T 细胞在几种同源免疫功能正常的肿瘤模型中显著降低了肿瘤负担并显著延长了生存期。此外，我们发现 Sirf CAR-T 细胞诱导了更多的中央记忆 T 细胞（T），并改善了 CAR-T 细胞在肿瘤组织中的持久性，同时降低了 CAR-T 细胞表面 PD-1 的表达。此外，我们证明 Sirf CAR-T 细胞可以通过减少髓样来源的干细胞以及增加肿瘤组织中 CD11c 树突状细胞和 M1 型巨噬细胞来调节肿瘤微环境。
总之，我们的研究结果表明，CD47 阻断剂 SIRPα-Fc 增强了 CAR-T 细胞的抗肿瘤疗效，并提出阻断 CD47/SIRPα 信号对 CAR-T 细胞功能的影响，这为通过合理化 CD47 阻断剂和 CAR-T 细胞治疗的组合来成功进行癌症免疫治疗提供了新策略。
