PT  - JOURNAL ARTICLE
AU  - Currie, Andrew J.
AU  - Prosser, Amy
AU  - McDonnell, Alison
AU  - Cleaver, Amanda L.
AU  - Robinson, Bruce W. S.
AU  - Freeman, Gordon J.
AU  - van der Most, Robbert G.
TI  - 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
AID  - 10.4049/jimmunol.0901060
DP  - 2009 Dec 15
TA  - The Journal of Immunology
PG  - 7898--7908
VI  - 183
IP  - 12
4099  - http://www.jimmunol.org/content/183/12/7898.short
4100  - http://www.jimmunol.org/content/183/12/7898.full
SO  - J. Immunol.2009 Dec 15; 183
AB  - 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.