The Immune System Strikes Back: Cellular Immune Responses against Indoleamine 2,3-dioxygenase

Rikke Bæk Sørensen, Linda Berge-Hansen, Niels Junker, Christina Aaen Hansen, Sine Reker Hadrup, Ton N. M. Schumacher, Inge Marie Svane, Jürgen C. Becker, Per Thor Straten, Mads Hald Andersen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background: The enzyme indoleamine 2,3-dioxygenase (IDO) exerts an well established immunosuppressive function in cancer. IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the present study, we tested the notion whether IDO itself may be subject to immune responses.Methods and Findings: The presence of naturally occurring IDO-specific CD8 T cells in cancer patients was determined by MHC/peptide stainings as well as ELISPOT. Antigen specific cytotoxic T lymphocytes (CTL) from the peripheral blood of cancer patients were cloned and expanded. The functional capacity of the established CTL clones was examined by chrome release assays. The study unveiled spontaneous cytotoxic T-cell reactivity against IDO in peripheral blood as well as in the tumor microenvironment of different cancer patients. We demonstrate that these IDO reactive T cells are indeed peptide specific, cytotoxic effector cells. Hence, IDO reactive T cells are able to recognize and kill tumor cells including directly isolated AML blasts as well as IDO-expressing dendritic cells, i.e. one of the major immune suppressive cell populations.Conclusion: IDO may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies. Furthermore, as emerging evidence suggests that IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, IDO-based immunotherapy holds the promise to boost anti-cancer immunotherapy in general.
Original languageEnglish
Article numbere6910
JournalP L o S One
Volume4
Issue number9
ISSN1932-6203
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common SW480 cell line cell_line human colon cancer cells MDA-MB-231 cell line cell_line human breast cancer cells HCT-116 cell line cell_line human colon cancer cells CAMA-1 cell line cell_line human breast cancer cells
  • indoleamine 2,3-dioxygenase IDO expression immunogenicity
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 10802, Enzymes - General and comparative studies: coenzymes
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 15506, Urinary system - Pathology
  • 16506, Reproductive system - Pathology
  • 18506, Integumentary system - Pathology
  • 24003, Neoplasms - Immunology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24010, Neoplasms - Blood and reticuloendothelial neoplasms
  • 34502, Immunology - General and methods
  • 34508, Immunology - Immunopathology, tissue immunology
  • Clinical Immunology
  • Enzymology
  • Oncology
  • AML acute myeloid leukemia neoplastic disease, immune system disease, blood and lymphatic disease immunology
  • breast cancer Breast Neoplasms (MeSH) neoplastic disease, reproductive system disease/female immunology
  • melanoma Melanoma (MeSH) neoplastic disease, integumentary system disease immunology
  • renal cell carcinoma Carcinoma, Renal Cell (MeSH) Kidney Neoplasms (MeSH) urologic disease, neoplastic disease immunology
  • cellular immune response
  • Biochemistry and Molecular Biophysics
  • Human Medicine, Medical Sciences
  • CD8 T cells immune system
  • cytotoxic T lymphocytes CTL immune system, blood and lymphatics
  • dendritic cells immune system
  • immune system immune system
  • PBMC peripheral blood mononuclear cell immune system, blood and lymphatics
  • chrome release assay laboratory techniques
  • ELISPOT laboratory techniques, immunologic techniques
  • MHC/peptide staining laboratory techniques

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