嵌合抗原受体（CAR）-T细胞疗法是特定造血系统恶性肿瘤的有效治疗策略。然而，该创新疗法在治疗实体肿瘤中的阳性结果受到免疫抑制性肿瘤微环境（TME）的限制，在该环境下，程序性死亡-1（PD-1）/PD-L1的信号直接抑制T细胞的应答。虽然检查点靶向免疫疗法成功增加了控制肿瘤生长所需的T细胞数量，但该效果受到TME中骨髓来源抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）的作用所减弱。以往的研究已证实，靶向巨噬细胞上表达的触发受体2（TREM2）和MDSC可以增强抗PD-1免疫疗法的效果。我们构建了用于结直肠癌（CRC）特异性抗原的相关基因Carcinoembryonic Antigen (CEA)的CAR-T细胞，融入自源性PD-1-TREM2 scFv的单链可变片段（single-chain variable fragment，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，并且这些分泌的scFv阻断了存在于MDSCs和TAMs上的TREM2受体与配体的结合，减少了MDSCs和TAMs的比例，增强了T细胞的效应器功能，从而减轻了TME中的免疫耐药性。PD-1-TREM2 scFv分泌的CAR-T细胞在一个皮下CRC小鼠模型中与PD-1 scFv分泌的CAR-T疗法相比，对肿瘤的消除效果显著增强。此外，由CAR-T细胞分泌的PD-1-TREM2 scFv仍保持在肿瘤内，并展现出更长的半衰期。综上，这些结果表明PD-1-TREM2 scFv分泌的CAR-T细胞在CRC治疗中具有强大的潜力。© 2023 BioMed Central Ltd., part of Springer Nature.

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.© 2023. BioMed Central Ltd., part of Springer Nature.