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Blood. 2010 Oct 7;116(14):2484-93. doi: 10.1182/blood-2010-03-275446. Epub 2010 Jun 22.

Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.

Author information

  • 1Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.

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.

PMID:
20570856
[PubMed - indexed for MEDLINE]
PMCID:
PMC2953885
Free PMC Article

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