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

Qing Zhou, Meghan E. Munger, Steven L. Highfill, Jakub Tolar, Brenda J. Weigel, Megan Riddle, Arlene H. Sharpe, Daniel A. Vallera, Miyuki Azuma, Bruce L. Levine, Carl H. June, William J Murphy, David H. Munn, Bruce R. Blazar

Research output: Contribution to journalArticle

169 Scopus citations

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 Teffector 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.

Original languageEnglish (US)
Pages (from-to)2484-2493
Number of pages10
JournalBlood
Volume116
Issue number14
DOIs
StatePublished - Oct 7 2010

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zhou, Q., Munger, M. E., Highfill, S. L., Tolar, J., Weigel, B. J., Riddle, M., Sharpe, A. H., Vallera, D. A., Azuma, M., Levine, B. L., June, C. H., Murphy, W. J., Munn, D. H., & Blazar, B. R. (2010). Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood, 116(14), 2484-2493. https://doi.org/10.1182/blood-2010-03-275446