<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN"^^ . "Naturally occurring CD4+CD25+Foxp3+ regulatory T cells (Treg) have been shown to suppress immune responses, including anti-tumor immunity. Strategies of manipulating Treg in cancer patients are currently evaluated in clinical trials with the aim of enhancing the efficiency of vaccinations, targeting the adaptive arm of immunity. Many tumors, however, lose expression of MHC class I and thus become protected from CD8+ T cell-mediated recognition and elimination. Such types of tumors can still be efficiently eliminated by cells of the innate immune system, in particular NK cells, through antigen- and MHC class I-independent mechanisms. The role of Treg in the rejection of tumors, which are predominantly under the control of innate immune cells has been poorly addressed so far. In this study, we investigated the influence of Treg on the immune response against the MHC class I-deficient mouse lymphoma RMA-S after subcutaneous injection. We showed that Treg accumulate in the tumor tissue and lymphoid organs of tumor-bearing animals. Treg depletion upon application of an anti-CD25 monoclonal antibody led to the rejection of high tumor cell numbers, which in contrast grew progressively in untreated mice. Our experiments demonstrated that NK1.1+ cells, CD8+ and CD4+CD25- T cells are recruited in high cell numbers to the tumor site in the absence of Treg and that all of these three cell populations contribute to RMA-S tumor rejection. Primary immune responses elicited during Treg depletion led to the generation of protective immunological memory; rechallenge of mice that had rejected the initial tumor with either RMA S or MHC class I-sufficient RMA tumor cells resulted in immediate tumor rejection. Furthermore, we showed that IFN-γ is produced in higher amounts by the tumor-infiltrating lymphocytes in the absence of Treg. Neutralization of IFN-γ completely abrogated the tumor rejection observed after Treg depletion, which correlated with the inhibition of accumulation of leukocytes at the tumor site. Among the tumor-infiltrating leukocytes, macrophages constituted the major cell population infiltrating the RMA-S tumor tissue in the absence of Treg. Tumor-infiltrating macrophages from Treg depleted mice expressed increased amounts of MHC class II and produced highly enhanced levels of chemokines and pro-inflammatory cytokines as compared to control mice. Macrophages isolated from the tumors also inhibited tumor cell proliferation through a mechanism independent of iNOS, PGE2 and IDO. In conclusion, this study supports a role for Treg in blunting the immune response to a MHC class I-deficient tumor target, by interfering with leukocyte accumulation at the tumor site. In addition, high numbers of activated tumor-infiltrating macrophages correlated with tumor rejection in the absence of Treg. These data identify macrophages as novel potential targets for Treg mediated immune suppression in cancer. In the second part of this study, we aimed at defining further mechanisms controlling the immune response against the MHC class I-deficient RMA-S tumor. For this purpose, we focused on the role of endogenously produced type I IFN. Although exogenously administered type I IFN have been used to treat various types of cancer, their endogenous production and function during an anti-tumor response has not been extensively studied. We studied the growth of RMA-S tumor in mice that cannot respond to type I IFN (IFNAR1-/- mice) and observed an acceleration in the tumor growth. In addition, we prepared bone marrow chimeras in which either the hematopoietic or the non-hematopoietic cells cannot respond to type I IFN and we found that type I IFN responsiveness is required in both compartments. Namely, IFNAR1 was important for NK cell cytotoxicity and proper development of the vessel network in the tumor tissue. In contrast, its absence did neither affect macrophage effector functions nor accumulation of leukocytes within the tumor tissue. In summary, endogenously produced type I IFN contribute to the control of the MHC class I deficient RMA-S tumor growth, via targeting both the hematopoietic and non-hematopoietic compartments, and regulate NK cell activity and tumor vessel formation. "^^ . "2008" . . . . . . . . "Ioanna Evdokia"^^ . "Galani"^^ . "Ioanna Evdokia Galani"^^ . . . . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (PDF)"^^ . . . "PhD_thesis_Ioanna_Galani.pdf"^^ . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Enhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #8497 \n\nEnhancing anti-tumor immunity to MHC class I-deficient tumors: role of regulatory T cells and type I IFN\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .