@article {542276, title = {Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.}, journal = {Blood}, volume = {116}, number = {14}, year = {2010}, month = {2010 Oct 7}, pages = {2484-93}, abstract = {Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8(+) cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8(+) T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.}, keywords = {Animals, Antibodies, Monoclonal, Antigens, CD274, Antigens, CD8, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute, Lymphocyte Depletion, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory}, issn = {1528-0020}, doi = {10.1182/blood-2010-03-275446}, author = {Zhou, Qing and Munger, Meghan E and Highfill, Steven L and Tolar, Jakub and Weigel, Brenda J and Riddle, Megan and Sharpe, Arlene H and Vallera, Daniel A and Azuma, Miyuki and Levine, Bruce L and June, Carl H and Murphy, William J and Munn, David H and Blazar, Bruce R} }