Cancer Immunology, Immunotherapy

, Volume 56, Issue 9, pp 1417–1428

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

  • Henrik Søndergaard
  • Klaus S. Frederiksen
  • Peter Thygesen
  • Elisabeth D. Galsgaard
  • Kresten Skak
  • Paul E. G. Kristjansen
  • Niels Ødum
  • Michael Kragh
Original Article

DOI: 10.1007/s00262-007-0285-4

Cite this article as:
Søndergaard, H., Frederiksen, K.S., Thygesen, P. et al. Cancer Immunol Immunother (2007) 56: 1417. doi:10.1007/s00262-007-0285-4

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.

Keywords

Interleukin-21Tumor infiltrating lymphocytesCancerMelanomaRenal cell carcinoma

Abbreviations

IL-21

Interleukin 21

i.v.

Intravenous

i.p.

Intraperitoneal

s.c.

Subcutaneous

TILs

Tumor infiltrating lymphocytes

NK cells

Natural killer cells

CTLs

Cytotoxic T lymphocytes

AOI

Area of interest

AUC

Area under the curve

WT

Wild type

LN

Lymph node

IP-10

Interferon-inducible protein 10

MIG

Monokine induced by interferon gamma

I-TAC

Interferon-inducible T cell alpha chemoattractant

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Henrik Søndergaard
    • 1
  • Klaus S. Frederiksen
    • 2
  • Peter Thygesen
    • 3
  • Elisabeth D. Galsgaard
    • 1
  • Kresten Skak
    • 1
  • Paul E. G. Kristjansen
    • 4
  • Niels Ødum
    • 5
  • Michael Kragh
    • 1
  1. 1.Department of Cancer Pharmacology, Biopharmaceuticals Research UnitNovo Nordisk A/SMåløvDenmark
  2. 2.Department of Molecular Genetics, Biopharmaceuticals Research UnitNovo Nordisk A/SBagsværdDenmark
  3. 3.Department of Exploratory ADME, Biopharmaceuticals Research UnitNovo Nordisk A/SMåløvDenmark
  4. 4.Department of Development Projects 05Novo Nordisk A/SBagsværdDenmark
  5. 5.Department of Molecular Biology and Physiology and Department of Medical Microbiology and ImmunologyUniversity of CopenhagenCopenhagenDenmark