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


RESULTS
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.


CONCLUSIONS
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.
Sørensen
Rikke Baek
RB
Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev, Denmark.
Berge-Hansen
Linda
L
Junker
Niels
N
Hansen
Christina Aaen
CA
Hadrup
Sine Reker
SR
Schumacher
Ton N M
TN
Svane
Inge Marie
IM
Becker
Jürgen C
JC
thor Straten
Per
P
Andersen
Mads Hald
MH
D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism
D000951:Antigens, Neoplasm; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010455:Peptides