In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5.
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. Cytotoxic 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-alpha (TNF alpha), 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-TNF alpha 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 Fc gamma RII (CD32), HLA-DR, CR3 (CD11b) 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.
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
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Rivoltini
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Viggiano
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Spinazzè
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Santoro
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Colombo
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Takatsu
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Parmiani
D000920:Antibody-Dependent Cell Cytotoxicity; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D003602:Cytotoxicity, Immunologic; D004804:Eosinophils / Q000276:immunology*; D005069:Evaluation Studies as Topic; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D015848:Interleukin-5 / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007376:Interleukin-2; D015848:Interleukin-5; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor