Effects of interleukin-12 on interferon-gamma production by peripheral blood and tumor infiltrating T-lymphocytes from renal cell carcinoma patients: Evidence of impaired secretion

Interleukin-12 (IL-12) is a heterodimeric cytokine that is a potent activator of T cells and natural killer cells and has significant antitumor activity in a variety of murine tumor models. Recent studies suggest that tumor regression induced by IL-12 is dependent on T cells and the production of IFN-γ. We have examined in vitro the effects of IL-12 on the production of IFNy by tumor infiltrating lymphocytes (TIL) isolated from patients with renal cell carcinoma in comparison to matched peripheral blood T cells (RCC-PBL) and T cells from normal individuals (NL-PBL). The production of IFN-r was impaired in patient T cells following stimulation with IL-12 alone or with a co-stimulus (IL-2, anti-CD-3 monoclonal antibody). This poor response to IL-12 did not appear to be due to a lack of the expression of the βchain to the IL-12 receptor. Additional experiments demonstrated that the supernatant fluid from RCC expiants could suppress the production of IFNy by T cells derived from the peripheral blood of normal volunteers. Stimulation of T cells in the presence of RCC supernatant for 48 hours was sufficient to suppress IFNy secretion. In contrast, supernatants from uninvolved kidney tissue had minimal effect on T cell activation and IFNy secretion. These findings may become clinically important since human clinical trials with IL-12 are beginning.