title: Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer.
abstract: Tryptophan-2,3-dioxygenase (TDO) physiologically regulates systemic tryptophan levels in the liver. However, numerous studies have linked cancer with activation of local and systemic tryptophan metabolism. Indeed, similar to other heme dioxygenases TDO is constitutively expressed in many cancers. In the present study, we detected the presence of both CD8+and CD4+T-cell reactivity toward TDO in peripheral blood of patients with malignant melanoma (MM) or breast cancer (BC) as well as healthy subjects. However, TDO-reactive CD4+T cells constituted distinct functional phenotypes in health and disease. In healthy subjects these cells predominately comprised interferon (IFN)γ and tumor necrosis factor (TNF)-α producing Th1 cells, while in cancer patients TDO-reactive CD4+T-cells were more differentiated with release of not only IFNγ and TNFα, but also interleukin (IL)-17 and IL-10 in response to TDO-derived MHC-class II restricted peptides. Hence, in healthy donors (HD) a Th1 helper response was predominant, whereas in cancer patients CD4+T-cell responses were skewed toward a regulatory T cell (Treg) response. Furthermore, MM patients hosting a TDO-specific IL-17 response showed a trend toward an improved overall survival (OS) compared to MM patients with IL-10 producing, TDO-reactive CD4+T cells. For further characterization, we isolated and expanded both CD8+and CD4+TDO-reactive T cellsin vitro. TDO-reactive CD8+T cells were able to kill HLA-matched tumor cells of different origin. Interestingly, the processed and presented TDO-derived epitopes varied between different cancer cells. With respect to CD4+TDO-reactive T cells,in vitroexpanded T-cell cultures comprised a Th1 and/or a Treg phenotype. In summary, our data demonstrate that the immune modulating enzyme TDO is a target for CD8+and CD4+T cell responses both in healthy subjects as well as patients with cancer; notably, however, the functional phenotype of these T-cell responses differ depending on the respective conditions of the host.
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Mads Duus
authors.initials: MD
authors.lastname: Hjortsø
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Stine Kiaer
authors.initials: SK
authors.lastname: Larsen
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Kongsted
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Özcan
authors.initials: Ö
authors.lastname: Met
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Thomas Mørch
authors.initials: TM
authors.lastname: Frøsig
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Gitte Holmen
authors.initials: GH
authors.lastname: Andersen
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Shamaila Munir
authors.initials: SM
authors.lastname: Ahmad
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.affiliation: Department for Translational Dermato-Oncology (DKTK); Center for Medical Biotechnology (ZMB); University Hospital Essen; Universitätsstraße ; Essen, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Per Thor
authors.initials: PT
authors.lastname: Straten
authors.affiliation: Department of Hematology and Oncology; Center for Cancer Immune Therapy; University Hospital ; Herlev, Copenhagen, Denmark.
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
keywords: T cells; TDO; Th17; Tregs; immune regulation