Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Qing Zhou, Christoph Bucher, Meghan E. Munger, Steven L. Highfill, Jakub Tolar, David H. Munn, Bruce L. Levine, Megan Riddle, Carl H. June, Daniel A. Vallera, Brenda J. Weigel, Bruce R. Blazar

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Tumor-induced immune suppression can permit tumor cells to escape host immune resistance. To elucidate host factors contributing to the poor response of adoptively transferred tumor-reactive cytotoxic T lymphocytes (CTLs), we used a systemic model of murine acute myeloid leukemia (AML). AML progression resulted in a progressive regulatory T-cell (Treg) accumulation in disease sites. The adoptive transfer of in vitro - generated, potently lytic anti - AML-reactive CTLs failed to reduce disease burden or extend survival. Compared with non - AML-bearing hosts, transferred CTLs had reduced proliferation in AML sites of metastases. Treg depletion by a brief course of interleukin-2 diphtheria toxin (IL-2DT) transiently reduced AML disease burden but did not permit long-term survival. In contrast, IL-2DT prevented anti-AML CTL hypoproliferation, increased the number of transferred CTLs at AML disease sites, reduced AML tumor burden, and resulted in long-term survivors that sustained an anti-AML memory response. These data demonstrated that Tregs present at AML disease sites suppress adoptively transferred CTL proliferation, limiting their in vivo expansion, and Treg depletion before CTL transfer can result in therapeutic efficacy in settings of substantial preexisting tumor burden in which antitumor reactive CTL infusion alone has proven ineffective.

Original languageEnglish (US)
Pages (from-to)3793-3802
Number of pages10
JournalBlood
Volume114
Issue number18
DOIs
Publication statusPublished - Oct 29 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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