Elevated expression of PD-L1 in tumor cells mediates tumor-induced T-cell exhaustion and immune suppression; therefore protect the survival of tumor cells.
Together, our study demonstrates that the COX2/mPGES1/PGE<sub>2</sub> pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE<sub>2</sub> metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.
To further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice.
Lack of PD-L1 expression on malignant cells delayed tumor outgrowth in a CD8<sup>+</sup> T cell-mediated fashion, showing the importance of this molecule in immune suppression.
The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined.
In this issue of Cancer Cell, Lim et al. report that inflammation-induced and NF-κB-driven expression of deubiquitinating enzyme CSN5 leads to PD-L1 stabilization and immune suppression in tumors.
Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation.
Our data indicate that the B7-H1/PD-1 axis contributes to immune suppression in human HCC, with blockade of this pathway carrying important therapeutic implications.