REVERSIBLE ANERGY IN CIRCULATING LYMPHOCYTES OF CANCER-PATIENTS DURING INTERLEUKIN-2 THERAPY

Interleukin-2 plays a crucial role in enhancing the antitumor immune r esponse. Clinical trials, mainly in renal cell carcinoma and melanoma patients, have been carried out with encouraging results. Recent repor ts demonstrated that interleukin-2 therapy may depress the immune resp onse either in vitro or in vivo. We decided to monitor, in nine renal cancer patients, the proliferative responses and the parallel variatio ns in Ca2+ homeostasis of peripheral blood lymphocytes collected befor e, during and after the first cycle of a 3-day interleukin-2 systemic administration. The proliferative response to phytohemagglutinin or co ncanavalin A significantly dropped early during interleukin-2 infusion . Consistently, an impairment in mobilizing Ca2+, either from internal stores or via influx from outside, was observed. Results obtained wit h a mAb-alpha CD3 molecular complex strongly suggested that the TCR/CD 3 signal transduction pathway was defective. In contrast, no major var iations were observed in the general machinery controlling Ca2+ homeos tasis nor in the total Ca2+-releasable pool. Patients' lymphocytes, cu ltured in vitro for 3 days in medium alone, showed an almost complete recovery in their ability to respond to mitogens. In conclusion, we sh ow that interleukin-2 administration in cancer patients induces a reve rsible state of anergy in circulating lymphocytes, assessed both by th e reduction in the proliferative response and the block of the mitogen -activated intracellular Ca2+ signalling.