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

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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.

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Abbreviations

FDA:

Food and Drug Administration

rIL-2:

Recombinant interleukin-2

Tregs:

T regulatory cells

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Acknowledgments

This work was supported, in part, by National Cancer Institute (NCI) grant UM1 CA186716-01 (to Howard L. Kaufman) and utilized shared resources at Rutgers Cancer Institute of New Jersey supported by NCI P30CA72720.

Author contributions

Andrew Zloza and Howard L. Kaufman conceived and designed the experiments; Erica J. Huelsmann, Joseph R. Broucek, and Tasha Hughes performed the experiments; Andrew Zloza, Neal D. Dharmadhikaril, and Frederick J. Kohlhapp interpreted the data; Andrew Zloza, Neal D. Dharmadhikaril, Frederick J. Kohlhapp, and Howard L. Kaufman wrote the manuscript and all authors edited the manuscript.

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Correspondence to Howard L. Kaufman.

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Conflict of interest

Howard L. Kaufman has served as a consultant for Alkermes, Amgen, EMD Serono, Merck, Prometheus, and Sanofi and receives research funding from Bristol-Myers-Squibb, Merck, and Viralytics. All other authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Additional information

Data in part were previously presented as an abstract [J Immunother Cancer. 2013; 1(Suppl 1): P266] and poster at the 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC), National Harbor, MD, USA, November 8–10, 2013.

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Zloza, A., Dharmadhikari, N.D., Huelsmann, E.J. et al. Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma. Cancer Immunol Immunother 66, 9–16 (2017). https://doi.org/10.1007/s00262-016-1916-4

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