Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, 519000, Zhuhai, Guangdong, China.
Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, 519000, Zhuhai, Guangdong, China.
Mol Cancer. 2023 Aug 10;22(1):131. doi: 10.1186/s12943-023-01830-x.
Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy.
We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs.
We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life.
Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.
嵌合抗原受体 (CAR) -T 细胞疗法是一种针对特定血液恶性肿瘤的有效治疗策略。然而，这种新型疗法在治疗实体瘤方面的积极结果受到免疫抑制性肿瘤微环境 (TME) 的限制，其中检查点程序性死亡-1 (PD-1)/PD-L1 的信号直接抑制 T 细胞反应。尽管检查点靶向免疫疗法成功增加了产生以控制肿瘤生长的 T 细胞数量，但 TME 中的髓系来源抑制细胞 (MDSCs) 和肿瘤相关巨噬细胞 (TAMs) 的作用减轻了这种效果。先前的研究证实，针对 TAMs 和 MDSCs 上的触发受体表达在髓样细胞 2 (TREM2) 可增强抗 PD-1 免疫疗法的效果。
我们构建了针对结直肠癌 (CRC) 特异性抗原的癌胚抗原 (CEA)-特异性 CAR-T 细胞，该细胞带有自分泌 PD-1-TREM2 单链可变片段 (scFv)，以靶向 PD-1/PD-L1 通路、MDSCs 和 TAMs。
我们发现 PD-1-TREM2 靶向 scFv 抑制了 PD-1/PD-L1 通路的激活。此外，这些分泌的 scFvs 阻断了配体与 MDSCs 和 TAMs 上存在的 TREM2 受体的结合，减少了 MDSCs 和 TAMs 的比例，并增强了 T 细胞效应功能，从而减轻了 TME 中的免疫抵抗。与 PD-1 scFv 分泌的 CAR-T 治疗相比，PD-1-TREM2 scFv 分泌的 CAR-T 细胞在皮下 CRC 小鼠模型中导致肿瘤的高度有效消除。此外，CAR-T 细胞分泌的 PD-1-TREM2 scFv 仍局限于肿瘤内，并表现出延长的半衰期。
综上所述，这些结果表明 PD-1-TREM2 scFv 分泌的 CAR-T 细胞具有作为 CRC 有效治疗的强大潜力。
