Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+ T cell expansion in an immunocompetent mouse model |
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Authors: | David M Foureau Iain H McKillop Chase P Jones Asim Amin Richard L White Jonathan C Salo |
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Institution: | (1) Department of General Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA;(2) Blumenthal Cancer Center, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA;(3) Department of Medicine, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA; |
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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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