Insight into the mechanism(s) through which TNF promotes the generation of T cell-mediated antitumor cytotoxicity by tumor bearer splenic cells.

We have shown previously that addition of TNF to stimulation cultures of MOPC-315 tumor bearer splenic cell suspensions containing metastatic tumor cells capable of secreting TGF-beta greatly enhances the generation of anti-MOPC-315 lytic activity by their CD8+ T cells. The current studies were undertaken to gain some insight into the mechanism(s) through which TNF potentiates the in vitro generation of anti-MOPC-315 cytotoxicity by such tumor bearer splenic cells. Here we show that TNF is capable of 1) preventing completely the inhibitory activity of TGF-beta for CTL generation when both cytokines are added at the time of initiation of a 5-day stimulation culture and 2) reversing at least part of the inhibitory activity of TGF-beta when TNF is added as late as 3 days after TGF-beta addition.

Transforming growth factor-beta-mediated down-regulation of antitumor cytotoxicity of spleen cells from MOPC-315 tumor-bearing mice engaged in tumor eradication following low-dose melphalan therapy.

We have previously shown that treatment of mice bearing a large MOPC-315 plasmacytoma with a low dose of the anticancer drug melphalan (L-phenylalanine mustard; L-PAM) results in the acquisition of a potent CD8+ T-cell-mediated anti-MOPC-315 cytotoxic T lymphocyte (CTL) activity by the hitherto immunosuppressed tumor bearers, and this immunity contributes to complete tumor eradication. In the studies presented here, we sought to determine how the acquisition of this antitumor immunity following low-dose chemotherapy is possible, in light of the report that MOPC-315 tumor cells produce transforming growth factor-beta (TGF-beta), an immunosuppressive cytokine that can down-regulate the generation of CTL responses. We found that the acquisition of CTL activity following low-dose L-PAM therapy is not due to a chemotherapy-induced decrease in the sensitivity of MOPC-315 tumor bearer spleen cells to TGF-beta-mediated inhibition of CTL generation.