Study On The Anti-Pancreatic Cancer Of NKG2D-CAR T Cells After Co-Expression Of PD-1/IL-7R Chimeric Receptor

Pancreatic cancer is a tumor from the digestive tract and highly invasive.Due to its complex tumor microenvironment,there is no good treatment.As a promising anti-tumor product,CAR T cell therapy has made a huge breakthrough in the treatment of hematological tumors,but the effect on solid tumors(such as pancreatic cancer)is not satisfactory.It is very important to overcome the tumor microenvironment to enhance the anti-solid tumor effect of CAR T cells.NKG2D/NKG2 DL can be a better target for CAR T therapy because its ligands are significantly upregulated in tumor tissues and slightly expressed in normal tissues.CAR T cells targeting this target have been reported in many clinical studies for the treatment of tumors,with good safety and effectiveness.In the complex tumor microenvironment,PD-1 plays a very important role in the process of T cell exhaustion,and its ligand PD-L1 is highly expressed in tumor cells.At the same time,IL-7 can promote the differentiation of T cells into memory cells,but not responded to in the tumor microenvironment,thus PD-1 and IL-7R lead to distinct differentiation fates of tumor-infiltrating immune cells.This study focuses on PD-1 and IL-7R signaling,it is expected to reverse PD-1 signaling to IL-7 signaling by co-expression of PD-1/IL-7R chimeric receptors in NKG2D-CAR T cells to enhances the function of CAR T cells.Our results showed that the co-expression of PD-1/IL-7R chimeric receptor could cause the activation of IL-7R-related pathways such as NF-κB,Akt-m TOR,and MAPK in NKG2D-CAR T,thereby improving the cell proliferation,enhancing its killing ability,and increasing of the proportion of memory T cells,which suggested the stronger and long-term anti-tumor ability.In vivo experiment also indicated that PD-1/IL-7R-NKG2D-CAR T cells had stronger effect of anti-pancreatic cancer,and co-expression of PD-1/IL-7R enhanced the proliferation and activation of CD8+T cells in vivo.Therefore,the combination of PD-1/IL-7R chimeric receptor can provide ideas for the treatment of CAR T in solid tumors.