CD39, expressed by tumor infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger anti-tumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active anti-tumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus surface protein (HBVs)-specific chimeric antigen receptor T-cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8 T cells. We subsequently assessed their anti-tumor efficiency mainly with a co-culture system for autologous HBVs-positive HCC organoid and T cells. We found that both CD39 HBVs-CAR-T and CD39 personalized tumor-reactive CD8 T cells induced much more apoptosis in HCC organoids. Although the exhaustion status of CAR-T cells increased in CD39 CAR-T cells, triple knockdown of PD-1, Tim-3, and Lag-3 with shRNAs furtherly enhanced anti-tumor activity in CD39 CAR-T cells. Furthermore, these CD39 CAR-T cells exerted an increased secretion of interferon-γ and stronger anti-tumor effect in patient-derived xenograft mouse model. Our findings demonstrated that CD39 could be a promisingly biomarker to enrich active immune cells and become an indicator marker for evaluating the prognosis of immunotherapy for HCC patients.
About The Expert
Fan Zou
Jizhou Tan
Ting Liu
Bingfeng Liu
Yaping Tang
Hui Zhang
Jiaping Li
References
PubMed