Henrik Søndergaard:
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Interleukin (IL)-21 is a recently discovered cytokine with pleiotropic immunomodulatory effects and putative anti-tumor activity. This Ph.D. thesis examines the functions of IL-21 protein as cancer immunotherapy and the role of endogenous IL-21 in tumor immunity in preclinical mouse models. In Chapter 1, the specific objectives for the experimental work are introduced. Chapter 2 presents the theoretical background to cancer immunology and immunotherapy, including specific barriers to immunotherapy and current therapeutic advances. This is followed by a brief review of the mouse as a model organism for drug testing in cancer and immunology with specific considerations for IL-21. Chapter 3 contains four original manuscripts; a review manuscript introduces IL-21 and IL-21 receptor (IL-21R) immunobiology and reviews the current knowledge concerning IL-21 in cancer therapy and immunopathology, and the following 3 manuscripts present the experimental work of this thesis:
Paper I:
Søndergaard H. and Skak K. Interleukin 21: roles in immunopathology and cancer therapy. Tissue Antigens. 2009 Oct. 21, (Epub ahead of print)
Paper II:
Søndergaard H., Frederiksen K.S., Thygesen P., Galsgaard E.D., Skak K. Kristjansen P.E.G. and Kragh M. Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits syngeneic tumor growth. Cancer Immunol. Immunother. 2007, Sep;56(9):1417-28. Epub. 2007 Feb. 7
Paper III:
Søndergaard H., Galsgaard E.D., Bartholomæussen M., Ødum N. and Skak K. Intratumoral interleukin 21 increases anti-tumor immunity, tumor-infiltrating CD8+ T cell density and activity, and enlarges draining lymph nodes. J. Immunother. In press
Paper IV:
Søndergaard H., Coquet J.M., Uldrich A.P., McLaughlin N, Godfrey D.I., Sivakumar P.V. Skak K. and Smyth M.J. Endogenous interleukin 21 restricts CD8+ T cell expansion and is not required for tumor immunity. J. Immunol. 2009 Dec 1;183(11):7326-36. Epub 2009 Nov 13
Paper II and III focus on the anti-tumor effect of IL-21 protein therapy following intraperitoneal, subcutaneous and intratumoral administration in two preclinical mouse cancer models - B16 melanoma and RenCa renal cell carcinoma. Herein, the responsible effector cells for IL-21 anti-tumor activity are determined and the effects of IL-21 are evaluated on the density and activity of tumor infiltrating T cells and on tumor draining lymph nodes. Paper IV investigates the role of endogenous IL-21 in immunosurveillance, and primary and secondary tumor immunity using various experimental tumor models in IL-21- and IL-21R-deficient mice with focus on NK, NKT and CD8+ T cell responses.
The results obtained in Paper II-IV are discussed in chapter 4. Chapter 5 summarizes the main conclusions obtained in this thesis and chapter 6 outlines the perspectives for future research concerning IL-21 in cancer immunotherapy. A list of references is given at the end of the thesis (excluding those in Paper I-IV).