In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5

Authors

  • Licia Rivoltini,

    Corresponding author
    1. Divisions of Experimental Oncology D, Istituto Nazionale Tumori, 20133 Milan
    • Division of Experimental Oncology D, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy
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  • Mario Paolo Colombo,

    1. Divisions of Experimental Oncology D, Istituto Nazionale Tumori, 20133 Milan
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  • Giorgio Parmiani,

    1. Divisions of Experimental Oncology D, Istituto Nazionale Tumori, 20133 Milan
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  • Vincenzo Viggiano,

    Corresponding author
    1. Clinical Medicine III, University of Milan, School of Medicine, Ospedale Maggiore, 20122 Milan, Italy
    • Dr Viggiano performed the molecular studies while at the Centro “Catullo e Daniela Borgomainerio”, Istituto di Ricerche Farmacologiche “M. Negri”, Milan, Italy
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  • Silvia Spinazzè,

    Corresponding author
    1. Divisions of Medical Oncology, Istituto Nazionale Tumori, 20133 Milan
    • Service of Medical Oncology. Ospedale Regionale, 11100 Aosta, Italy
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  • Armando Santoro,

    1. Divisions of Medical Oncology, Istituto Nazionale Tumori, 20133 Milan
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  • Kiyoshi Takatsu

    1. Institute for Medical Immunology, Kumamoto University, Medical School, Honjo, 860 Kumamoto, Japan
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Abstract

Interleukin 2 (IL-2) administration is known to induce marked eosinophilia. To evaluate the potential role of eosinophils as anti-tumor effectors and to understand the direct or indirect effects of IL-2 on eosinophils, the physical and functional characteristics of eosinophils obtained during IL-2 therapy were compared with those of eosinophils obtained from the same patients before IL-2 administration, or from healthy donors. The treatment schedule consisted of subcutaneous (s.c.) injections of IL-2, and was performed in 7 patients with small-cell lung cancer (SCLC) in advanced stage. A marked increase of hypodense cells in peripheral blood was found to correlate with eosinophil activation in patients undergoing IL-2 therapy. Cyto-toxic activity of eosinophils against allogeneic tumor cells (SCLC, K562 and melanoma lines), as assessed by direct and antibody(Ab)-dependent cellular cytotoxicity (ADCC), was markedly increased during IL-2 therapy. Conversely, eosinophils obtained before treatment, like those of healthy donors, lacked any activity against tumor cells. Sera from IL-2-treated, but not from untreated, patients, significantly improved the in vitro survival and anti-tumor cytotoxicity of eosinophils from healthy donors. Comparable effects were obtained with eosinophils cultured with interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF) and, to a lesser extent, by tumor necrosis factor-α (TNFα), while no direct activity was mediated by IL-2. A 91% inhibition of eosinophil ADCC was found after pre-incubation of the sera of IL-2-treated patients with anti-IL-5 but not with anti-GM-CSF or anti-TNFα Ab. IL-5 mRNA expression was detected in peripheral-blood lymphocytes (PBL) obtained 4 hr after IL-2 injection during the second and third week of IL-2 therapy. Phenotypic analysis of eosinophils from IL-2-treated patients showed enhanced expression of activation markers, including Fcγ RII (CD32), HLA-DR, CR3 (CD I lb) and CRI (CD35). These findings suggest that a significant cytotoxicity against tumor cells can be mediated by eosinophils after indirect, IL-5-mediated in vivo activation by IL-2, and that eosinophils may be involved in the anti-tumor response(s) induced in vivo by IL-2.

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