Authors:
Currie, A. J., *Prosser, A., McDonnell, A., Cleaver, A. L., Robinson, B. W., Freeman, G. J., van der Most, R. G.
*equal first authorship
Authors notes:
J Immunol (2009) 183 12 7898-908
Keywords:
Dual control, antitumor CD8 T cells, programmed death-1/programmed death-ligand 1 pathway, immunosuppressive CD4 T cells, regulation and counterregulation
Abstract:
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.