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Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+ T cell expansion in an immunocompetent mouse model

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Abstract

Recombinant human interleukin-2 (rhIL-2) therapy is approved for treating patients with advanced melanoma yet significant responses are observed in only 10–15% of patients. Interleukin-2 induces Foxp3 expression in activated human CD8 T cells in vitro and expands circulating CD8 Foxp3+ T cells in melanoma patients. Employing IL-2 responsive (B16-F1, B16-BL6, JB/MS, MCA-205) and nonresponsive (JB/RH, B16-F10) subcutaneous tumor mouse models, we evaluated CD8 Foxp3+ T cell distribution and changes in response to rhIL-2 (50,000 U, i.p. or s.q., twice daily for 5 days). In tumor-free mice and subcutaneous tumor-bearing mouse models, CD8 Foxp3+ T cells were a rare but naturally occurring cell subset. Primarily located in skin-draining lymph nodes, CD8 Foxp3+ T cells expressed both activated T cell (CD28+, CD44+) and Treg (CTLA4+, PD1lo/var, NKG2A+/var) markers. Following treatment with rhIL-2, a dramatic increase in CD8 Foxp3+ T cell prevalence was observed in the circulation and tumor-draining lymph nodes (TD.LNs) of animals bearing IL-2 nonresponsive tumors, while no significant changes were observed in the circulation and TD.LNs of animals bearing IL-2 responsive tumors. These findings suggest expansion of CD8 Foxp3+ T cell population in response to rhIL-2 treatment may serve as an early marker for tumor responsiveness to immunotherapy in an immune competent model. Additionally, these data may provide insight to predict response in patients with melanoma undergoing rhIL-2 treatment.

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Acknowledgments

This work was supported in part by a grant from The Carolinas Healthcare Foundation (DMF). JB/MS and JB/RH were donated by Dr. Esteban Celis (H. Lee Moffitt Cancer Center, Tampa FL). The MCA-205 cell line was a generous gift from Dr. Alfred Chang (University of Michigan, Ann Arbor, MI). Highly purified rhIL-2 was a gift from Chiron Corporation (Emeryville, CA). We thank Perla Nunes for technical assistance with flow cytometry.

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Authors and Affiliations

  1. Department of General Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA

    David M. Foureau, Iain H. McKillop, Chase P. Jones, Richard L. White & Jonathan C. Salo

  2. Blumenthal Cancer Center, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA

    David M. Foureau, Asim Amin, Richard L. White & Jonathan C. Salo

  3. Department of Medicine, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA

    Asim Amin

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  1. David M. Foureau
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  2. Iain H. McKillop
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Correspondence to Iain H. McKillop.

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Foureau, D.M., McKillop, I.H., Jones, C.P. et al. Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+ T cell expansion in an immunocompetent mouse model. Cancer Immunol Immunother 60, 1347–1356 (2011). https://doi.org/10.1007/s00262-011-1035-1

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  • DOI: https://doi.org/10.1007/s00262-011-1035-1

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