title: Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors.
abstract: 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.
authors.affiliation: Department of Cancer Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Nordisk Park F6.2.30, DK, Måløv, Denmark. hris@novonordisk.com
authors.forename: Henrik
authors.initials: H
authors.lastname: Søndergaard
authors.forename: Klaus S
authors.initials: KS
authors.lastname: Frederiksen
authors.forename: Peter
authors.initials: P
authors.lastname: Thygesen
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Galsgaard
authors.forename: Kresten
authors.initials: K
authors.lastname: Skak
authors.forename: Paul E G
authors.initials: PE
authors.lastname: Kristjansen
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D007378:Interleukins / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology*; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D000970:Antineoplastic Agents; D007378:Interleukins; D000098546:Interleukin-21