Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation

Tumors have evolved multiple mechanisms to evade immune destruction. One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1; B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. However, PD-L1 blockade only marginally affected tumor growth and was associated with the emergence of activated programmed death-1+ ICOS+ CD4 T cells in tumor-draining lymph nodes, whereas few activated CD8 T cells were present. Full activation of antitumor CD8 T cells, characterized as programmed death-1+ ICOS+ Ki-67+ and displaying CTL activity, was only observed when CD4 T cells were depleted, suggesting that a population of suppressive CD4 T cells exists. ICOS+ foxp3+ regulatory T cells were found to be regulated through PD-L1, identifying one potentially suppressive CD4 T cell population. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies.