Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in Colorectal cancer

Background: Chimeric antigen receptor- T (CAR-T) cell therapy is an efficient therapeutic strategy for specific hematological malignancies. However, positive outcomes of this novel therapy in treating solid tumors are restricted by the immunosuppressive tumor microenvironment (TME), wherein, checkpoint molecular programmed death-1 (PD-1)/PD-L1 signaling directly inhibits T-cell responses. Although checkpoint 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) present 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. Methods Therefore, we constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. Results 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. Meanwhile, the scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. Conclusions The PD-1-TREM2 scFv-secreting CAR-T cells exhibited substantially potent anti-tumor effects, evidenced by highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.