Abstract
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.
Highlights
Colorectal cancer (CRC) is the world’s third most common malignancy, ranking fourth in the world among cancer deaths
EpCAM is an antigen expressed on most normal epithelial cells as well as in gastrointestinal carcinomas (Trzpis et al, 2007)
EpCAM shows significantly increased expression in the metastatic stage of cancer compared with primary tumors, indicating that EpCAM is a potential therapeutic target for metastatic cancer. These results suggest that EpCAM shows increased expression in cancer cells compared with normal cells and that it is associated with cancer progression and metastasis
Summary
Colorectal cancer (CRC) is the world’s third most common malignancy, ranking fourth in the world among cancer deaths. The number of people with colorectal cancer is expected to increase by 60% by 2030, with the number of new cases expected to exceed two million per year and the number of deaths to exceed 1.1 million (Bray et al, 2018). With the emergence of new chemotherapy and small molecule drugs in clinical applications, metastasis and advanced colorectal cancer can be treated, but there is still a lack of effective treatment for colorectal cancer, and the strong side effects of the drugs make it difficult to improve the quality of life for patients (McQuade et al, 2017). Adoptive cell therapy (ACT) is an efficient and personalized cancer treatment that uses T cells that target tumor antigens to perform natural functions to kill tumor cells. We explored chimeric antigen receptor (CAR) T-cell therapy by building suitable CAR T cells to examine their effect on colon cancer tumor cells and the relevant influencing factors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
