INHIBITION OF PROTEIN-TYROSINE KINASES OR PROTEIN-KINASE-C PREVENTS NONSPECIFIC KILLER T-LYMPHOCYTE-MEDIATED TUMORICIDAL ACTIVITY

The signal transduction events which govern major histocompatibility c omplex-unrestricted tumour cell destruction by nonspecific killer T ly mphocytes induced with anti-CD3 antibody have not yet been determined. in this study we used pharmacologic inhibitors to investigate the rol e of protein tyrosine kinases (PTK) and protein kinase C (PKC) in this process. The PTK-inhibitors herbimycin A, genistein, and methyl 2,5-d ihydroxycinnamate blocked anti-CD3-activated killer T (AK-T) lymphocyt e-mediated killing of tumour target cells. The PKC-inhibitors staurosp orine, calphostin C, and myristoylated PKC pseudosubstrate peptide, as well as PKC desensitization by phorbol 12-myristate 13-acetate pretre atment, also suppressed the cytolytic effector function of AK-T lympho cytes. Lack of tumoricidal activity was not due to reduced AK-T lympho cyte binding to tumour target cells but was associated with the abroga tion of granule exocytosis, indicating that PTK and PKC are involved i n the postbinding process which results in delivery of the 'lethal hit ' by AK-T lymphocytes. (C) 1997 Elsevier Science B.V.