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

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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.

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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

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Acknowledgement

We would like to thank Heidi Winther, Bodil Andreasen, Birte Jørgensen and Kirsten Meeske for technical assistance with the experiments, and Mark Smyth for valuable discussion of the manuscript.

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Authors and Affiliations

  1. Department of Cancer Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Nordisk Park F6.2.30, DK, 2760, Måløv, Denmark

    Henrik Søndergaard, Elisabeth D. Galsgaard, Kresten Skak & Michael Kragh

  2. Department of Molecular Genetics, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Alle, DK, 2880, Bagsværd, Denmark

    Klaus S. Frederiksen

  3. Department of Exploratory ADME, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Nordisk Park, DK, 2760, Måløv, Denmark

    Peter Thygesen

  4. Department of Development Projects 05, Novo Nordisk A/S, Novo Alle, DK, 2880, Bagsværd, Denmark

    Paul E. G. Kristjansen

  5. Department of Molecular Biology and Physiology and Department of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark

    Niels Ødum

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  1. Henrik Søndergaard
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Correspondence to Henrik Søndergaard.

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Søndergaard, H., Frederiksen, K.S., Thygesen, P. et al. Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors. Cancer Immunol Immunother 56, 1417–1428 (2007). https://doi.org/10.1007/s00262-007-0285-4

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