Colorectal cancer (CRC) patients are still lacking viable treatments.
Chimeric antigen receptor (CAR) T cells have shown promise in
hematologic malignancies, but their efficacy in solid
tumors has been limited due to the immunosuppressive tumor microenvironment. We found that
cancer antigen-
EpCAM expression increased in the metastatic stage compared with the primary stage in
cancers and the activation of Wnt and TGFβ pathways was positively correlated with
EpCAM expression in multiple
cancers, including
colorectal cancer. We constructed CAR T cells targeting
EpCAM that successfully showed selective cytotoxicity in highly
EpCAM-expressing
cancer cell lines. The combination of
EpCAM CAR-T with the Wnt inhibitor-hsBCL9CT-24 displayed synergetic effect against
EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9CT-24 treatment could modulate the
tumor environment and improve infiltration of T cells, while possibly promoting the effector T cells at the early stages and postponing the exhaustion of CAR T cells at advanced stages. Overall, these results demonstrated that the combination of
EpCAM CAR T-cell therapy with the Wnt inhibitor can overcome the limitations of CAR T cells in treating solid
tumors.