Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2007-09, Vol.56 (9), p.1417-1428
• Main Authors: Søndergaard, Henrik, Frederiksen, Klaus S, Thygesen, Peter, Galsgaard, Elisabeth D, Skak, Kresten, Kristjansen, Paul E G, Odum, Niels, Kragh, Michael
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antineoplastic Agents - therapeutic use; Antitumor agents; Bioavailability; Cancer therapies; Carcinoma, Renal Cell - therapy; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cytokines; Cytotoxicity; Female; Immunohistochemistry; Infusions, Parenteral; Injections, Subcutaneous; Interferon; Interleukin 21; Interleukins - therapeutic use; Kidney cancer; Kidney Neoplasms - therapy; Lymph nodes; Lymphatic system; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Medical prognosis; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monoclonal antibodies; Original; Proteins; Renal cell carcinoma; T-Lymphocyte Subsets - immunology; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-007-0285-4

Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and subsequently scored the densities of tumor infiltrating CD4(+) and CD8(+) T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account for the apparent increase in anti-tumor activity. Specific depletion of CD8(+) T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1(+) cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the density of tumor infiltrating CD8(+) T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density of tumor infiltrating CD8(+) T cells compared to i.p. administration. The densities of CD4(+) T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating CD8(+) T cells.