TY - JOUR
T1 - GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy
AU - Tan, Binghe
AU - Tu, Chuntian
AU - Xiong, Hao
AU - Xu, Yongqian
AU - Shi, Xiujuan
AU - Zhang, Xiaolin
AU - Yang, Ruijie
AU - Zhang, Na
AU - Lin, Boxu
AU - Liu, Mingyao
AU - Qin, Juliang
AU - Du, Bing
N1 - Publisher Copyright:
© 2025 The American Society of Gene and Cell Therapy
PY - 2025/6/4
Y1 - 2025/6/4
N2 - Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of GITR ligand enhances the anti-tumor activity of CAR-T cells. Compared to prostate-specific membrane antigen-BB-Z (PSMA-BB-Z) CAR-T, PSMA-BB-Z-GITRL CAR-T cells have much more interferon (IFN)-γ, TNF-α, and interleukin (IL)-9 secretion, a higher proportion of central memory T (TCM) cells and T helper 9 (Th9) cells, less expression of exhaustion markers, and robust proliferation capacity. Consequently, PSMA-BB-Z-GITRL CAR-T cells exhibited more potent anti-tumor activity against established solid tumors in vivo than PSMA-BB-Z CAR-T cells. The results of the in vivo persistence experiment also indicated that PSMA-BB-Z-GITRL CAR-T cells exhibited much more retention in mouse blood, spleen, and tumor tissue than PSMA-BB-Z CAR-T cells 15 days after CAR-T cell therapy. In addition, PSMA-BB-Z-GITRL CAR-T cells produce higher levels of IFN-γ, TNF-α, and IL-9 in mouse blood, exhibiting a higher proportion of TCM cells and a lower proportion of Treg cells compared to PSMA-BB-Z CAR-T cells. Our results demonstrate that the overexpression of GITRL has important implications for improving CAR-T cell-based human solid tumor immunotherapy.
AB - Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of GITR ligand enhances the anti-tumor activity of CAR-T cells. Compared to prostate-specific membrane antigen-BB-Z (PSMA-BB-Z) CAR-T, PSMA-BB-Z-GITRL CAR-T cells have much more interferon (IFN)-γ, TNF-α, and interleukin (IL)-9 secretion, a higher proportion of central memory T (TCM) cells and T helper 9 (Th9) cells, less expression of exhaustion markers, and robust proliferation capacity. Consequently, PSMA-BB-Z-GITRL CAR-T cells exhibited more potent anti-tumor activity against established solid tumors in vivo than PSMA-BB-Z CAR-T cells. The results of the in vivo persistence experiment also indicated that PSMA-BB-Z-GITRL CAR-T cells exhibited much more retention in mouse blood, spleen, and tumor tissue than PSMA-BB-Z CAR-T cells 15 days after CAR-T cell therapy. In addition, PSMA-BB-Z-GITRL CAR-T cells produce higher levels of IFN-γ, TNF-α, and IL-9 in mouse blood, exhibiting a higher proportion of TCM cells and a lower proportion of Treg cells compared to PSMA-BB-Z CAR-T cells. Our results demonstrate that the overexpression of GITRL has important implications for improving CAR-T cell-based human solid tumor immunotherapy.
KW - CAR-T
KW - GITRL
KW - Th9
KW - central memory T
KW - solid tumor immunotherapy
UR - https://www.scopus.com/pages/publications/85217361991
U2 - 10.1016/j.ymthe.2025.01.036
DO - 10.1016/j.ymthe.2025.01.036
M3 - 文章
C2 - 39863927
AN - SCOPUS:85217361991
SN - 1525-0016
VL - 33
SP - 2789
EP - 2800
JO - Molecular Therapy
JF - Molecular Therapy
IS - 6
ER -
