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Non-Small Cell Lung Cancer-derived Soluble Mediators Enhance Apoptosis in Activated T Lymphocytes through an IB Kinase-dependent Mechanism¹

Department of Medicine and The Lung Cancer Research Program [R. K. B., Y. L., S. S., M. D., J. L., M. P., S. M. D.], Jonsson Comprehensive Cancer Center [R. K. B., S. M. D.], University of California at Los Angeles and Veterans Administration-Greater Los Angeles Health Care System, Los Angeles, California 90095

T lymphocyte survival is critical for the development and maintenance of an effective host antitumor immune response; however, the tumor environment can negatively impact T-cell survival. Lymphocytes exposed to tumor supernatants (TSNs) were evaluated for apoptosis after mitogen stimulation. TSN was observed to significantly enhance phorbol 12-myristate 13-acetate/ionomycin- and anti-CD3-stimulated lymphocyte apoptosis. Enhanced lymphocyte apoptosis was associated with an impairment of nuclear factor B nuclear translocation and diminished IB degradation. In lymphocytes stimulated after exposure to TSNs, cytoplasmic IB persisted as a result of alterations in IB kinase (IKK) activity. Accordingly, although there were no apparent differences in IKK component concentrations, lymphocytes preexposed to TSNs exhibited markedly reduced IKK activity. We conclude that non-small cell lung cancer-derived soluble factors promote apoptosis in activated lymphocytes by an IKK-dependent pathway.

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