A Study Discovered New Lentiviral Transfection Method that Preferentially Targets Solid Tumors

Both episode checkpoint inhibitors and adoptive cell therapy are novel immunotherapies that have the potential to treat solid tumors such as HBV-associated hepatocellular carcinoma (HCC), however, they all have their own drawbacks.

Recently, researchers from University College London and A*STAR in Singapore tried to combine these two methods to treat HCC by combining their respective advantages. They overcome T cell depletion by down-regulating the PD-1 signaling pathway of viral tumor antigen-specific T cells. Related research results are published in “Molecular Recalibration of PD-1 + Antigen-Specific T Cells from Blood and Liver”.

Researchers have developed a new lentiviral transfection method that preferentially targets endogenous or TCR rearranged antigen-specific CD8 T cells, using shRNA to knock out PD-1, and the anticancer effect of this T cell was subsequently examined. The researchers found that antigen-specific intrahepatic CD8 T cell transfection with lentiviral-shPD-1 significantly reduced PD-1 expression compared to the control lentiviral vector.

Knockdown of PD-1 in human T cells restores the anti-cancer effect of T cells and promotes its ability to kill cancer cells in 3D microdevices that mimic the pre-inflammatory liver microenvironment of PD-L1. However, once stimulated repeatedly, the knockdown of PD-1 leads to aging of T cells and triggers other costimulatory signaling pathways.

This study demonstrates that lentiviruses can target genetically engineered T cells that specifically target HBV-associated HCC viral antigens for functional gene editing. Knocking down PD-1 can enhance the ability of T cells to kill tumor cells in a short period of time, but the effect of this method is still limited due to the presence of other compensatory co-stimulatory signals and repeated stimulation leading to T cell senescence.