The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase

TY - JOUR

T1 - The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase

AU - Sørensen, Rikke Baek

AU - Berge-Hansen, Linda

AU - Junker, Niels

AU - Hansen, Christina Aaen

AU - Hadrup, Sine Reker

AU - Schumacher, Ton N M

AU - Svane, Inge Marie

AU - Becker, Jürgen C

AU - thor Straten, Per

AU - Andersen, Mads Hald

N1 - Keywords: Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Dendritic Cells; Epitopes; Histocompatibility Antigens Class I; Humans; Immune System; Immunosuppressive Agents; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase; Leukocytes, Mononuclear; Models, Biological; Peptides; T-Lymphocytes

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0006910

DO - 10.1371/journal.pone.0006910

M3 - Journal article

C2 - 19738905

SN - 1932-6203

VL - 4

SP - e6910

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

ER -