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.
Reference
- Itziar Otano et al. Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver, Molecular Therapy (2018).