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:
Søndergaard H. and Skak K. Interleukin 21: roles in immunopathology and cancer therapy. Tissue Antigens. 2009 Oct. 21, (Epub ahead of print)
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
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
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).