ABSTRACT
After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.
Subject(s)
Interleukin-2/therapeutic use , Lymphocyte Subsets/drug effects , Neoplasms/immunology , Antigens, CD/blood , Cytotoxicity, Immunologic , Humans , Immunophenotyping , Killer Cells, Lymphokine-Activated/physiology , Lymphocyte Subsets/immunology , Melanoma/immunology , Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Stomach Neoplasms/immunologyABSTRACT
The clinical use of interleukin-2 (IL-2) for generation and activation of cytotoxic lymphocytes lymphokine-activated killer cells (LAK) has principally demonstrated that tumors can be restricted by modulation of the immune system. However, innovative approaches are required to improve the therapeutic results. In this connection, combinations of IL-2 with other cytokines may be of interest to increase the numbers and cytotoxic activity of LAK. On the other hand, IL-2 itself mediates immune reactions and secretion of various cytokines. Therefore, we investigated the effect of interferon-alpha (IFN-alpha), IFN-gamma and tumor necrosis factor (TNF-alpha) on the induction of LAK activity by IL-2, and the induction of IFN-gamma and TNF-alpha by IL-2. LAK activity could not be enhanced by IFN-gamma and TNF-alpha, but was enhanced by IFN-alpha. This may in part be due to the fact that IL-2 itself induces high amounts of TNF-alpha and IFN-gamma. Besides the effect of IFN-alpha on LAK activity, an increased susceptibility of tumor cells for LAK in vitro could be achieved by preincubation of tumor cells with IFN-alpha. This mechanism seems not to be related to an increased expression of MHC class I and II antigens.
