Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma

Andrew Zloza, Neal D. Dharmadhikari, Erica J. Huelsmann, Joseph R. Broucek, Tasha Hughes, Frederick J. Kohlhapp, Howard L. Kaufman

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Recombinant interleukin-2 (rIL-2) is associated with objective responses in 15–20 % of patients with metastatic melanoma and renal cell carcinoma. More recently, rIL-2 has also demonstrated improved clinical activity in patients with melanoma. Given the toxicity of high-dose rIL-2 and the availability of many new immunotherapy agents, it has been suggested that lower doses of rIL-2 may be preferred for combination clinical studies. In order to determine the impact of low doses of rIL-2 on anti-tumor immunity and therapeutic effectiveness, we challenged C57BL/6 mice with poorly immunogenic B16-F10 melanoma and treated them with varying doses of rIL-2 (range 103–105 IU). Tumor growth at day 14 was significantly reduced when rIL-2 was administered at 10,000 (P < 0.02) and 100,000 (P < 0.02) IU doses, but tumor growth was significantly increased when mice were treated at 1000 IU rIL-2 (P < 0.02), as compared to placebo treatment. While the proportions of CD8+ and CD4+ T cells in the tumor were similar at all doses tested, the proportion of NK cells was decreased and the proportion of Tregs was increased in tumors exposed to low-dose rIL-2. The ratio of gp100-specific CD8+ to CD4+ regulatory T cells was increased in tumors treated at 10,000 and 100,000 IU of rIL-2 but was decreased at the 1000 IU dose compared to placebo-treated mice. These findings suggest that low-dose rIL-2 may impair host anti-tumor immunity and promote tumor growth. Early-phase adjuvant and combination clinical studies should include patient cohorts with higher doses of rIL-2.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalCancer Immunology, Immunotherapy
Volume66
Issue number1
DOIs
StatePublished - Jan 1 2017

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Keywords

  • CD8+ T cell
  • Cancer vaccines
  • Immunotherapy
  • Interleukin-2
  • Natural killer cell
  • Regulatory T cell

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  • Cite this

    Zloza, A., Dharmadhikari, N. D., Huelsmann, E. J., Broucek, J. R., Hughes, T., Kohlhapp, F. J., & Kaufman, H. L. (2017). Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma. Cancer Immunology, Immunotherapy, 66(1), 9-16. https://doi.org/10.1007/s00262-016-1916-4