Subcutaneous administration of interleukin-2 triggers Fcγ receptor I expression on human peripheral blood neutrophils in solid and hematologic malignancies

Freshly isolated human polymorphonuclear cells (PMNCs) constitutively express Fcγ receptor (FcγR) II and FcγRIII on the cell surface but not FcγRI. Cytokines such as interferon-γ (IFNγ), granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF trigger FcγRI expression on (PMNCs). Because PMNCs express interleukin (IL)-2 receptor, we investigated whether IL-2 can induce FcγRI expression on PMNCs isolated from IL-2-treated metastatic renal cell carcinoma (MRCC) and low-grade non-Hodgkin lymphoma (LGNHL) patients. Pretherapy flow cytometry analysis of Fc receptors on PMNCs did not show FcγRI expression. Interestingly, 3 days after therapy, PMNCs displayed a detectable amount of FcγRI on the cell surface. Kinetic studies on the in vivo effects of IL-2 on MRCC patients showed that FcγRI was transiently expressed, starting within 3-6 days of therapy, remaining expressed for 10-15 days, and rapidly declining, whereas such expression remained stable for months in LGNHL patients. In contrast, FcγRII was not affected. In addition, FcγRI + PMNCs coated in vitro with a bispecific antibody Fab anti-FcγRI x anti-HER-2/neu formed intercellular conjugates with a human HER-2/neu-transfected 3T3 cell line (HER-2/neu-3T3). Interleukin-2 treatment increased the number of FcγRIII low eosinophils, leading to a change in FcγRIII distribution among granulocyte cell subsets. In vitro IL-2 treatment of purified PMNCs failed to generate FcγRI expression, suggesting that IL-2 indirectly causes FcγRI expression. During the IL-2 administration, we did not observe significant changes in IFNγ serum level. In conclusion, our observation may he used to potentiate the antitumor effects of IL-2 in novel immunotherapy regimens, perhaps by redirecting FcγRI + PMNCs against cancer cells by heteroconjugate antibodies and monitoring the biologic activity of subcutaneous IL-2 in cancer patients.