Interferon-gamma production by T lymphocytes from renal cell carcinoma patients: Evidence of impaired secretion in response to interleukin-12

Interleukin-12 (IL-12) is a heterodimeric cytokine that enhances the cy cyt olytic activity, proliferation, and interferon-gamma (IFN-gamma) production by T lymphocytes and natural killer cells, and has significant antitumor a ctivity in a variety of murine tumor models. The induction of interferon (I FN)-gamma by IL-12 in tumor-bearing mice plays an important role in its ant itumor activity. We therefore examined the effects of IL-12 on IFN-gamma pr oduction by T cells derived from patients with renal cell carcinoma (RCC), including freshly isolated tumor infiltrating lymphocytes (T-TIL), matched peripheral blood T cells (T-PBL), and RCC-specific TIL lines. IL-12 alone i nduced IFN-gamma secretion by T cells from normal individuals and appeared to act synergistically with either IL-2 or anti-CD3 antibody. In contrast, it failed to stimulate significant IFN-gamma secretion by T-PBL and T-TIL f rom RCC patients. This unresponsive state in T-PBL appeared selective becau se IFN-gamma was produced when cells were stimulated with either phytohemag glutinin or anti-CD3 antibody. Moreover, costimulation through the T-cell r eceptor (TCR)/CD3 compiler or with IL-2 made T-PBL from RCC patients respon sive to IL-12, possibly secondary to the upregulation of IL-12R (beta chain ). A selective loss of IL-12-dependent production of IFN-gamma was also con sistently observed in two of three established RCC-specific TIL lines. Alth ough these cell lines did not respond to any concentration of IL-12, they d id produce IFN-gamma after ligation of the TCR/CD3 or stimulation with IL-2 . IL-12 also acted either syngeristically or additively with IL-2, anti-CD3 antibody, or autologous tumor cells to induce IFN-gamma production. The ob served decreases in IFN-gamma production in response to IL-12 may have a ne gative effect on the development of T-cell immunity. The clinical importanc e of these findings during in vivo administration of IL-12 remains to be de termined.