Importance of TNF production for the curative effectiveness of low dose melphalan therapy for mice bearing a large MOPC-315 tumor

Abstract

We have previously shown the importance of the acquisition of CD8+ T cell-dependent tumor-eradicating immunity for the curative effectiveness of low dose melphalan (L-PAM, L-phenylalanine mustard) for mice bearing a large MOPC-315 tumor. Here we show the importance of TNF production for the curative effectiveness of low dose L-PAM for such tumor-bearing mice. Studies regarding the mechanism(s) through which TNF exerts its antitumor effects in L-PAM-treated MOPC-315 tumor-bearing mice (L-PAM TuB mice) revealed that MOPC-315 tumor cells are not sensitive to the cytotoxic effects of TNF either before or after the chemotherapy. However, TNF is essential for the in vitro generation of potent CTL activity by CD8+ T cells from L-PAM TuB mice. Moreover, addition of exogenous TNF to in vitro stimulation cultures of spleen cells from untreated mice bearing a large MOPC-315 tumor resulted in the generation of a greatly enhanced CTL activity against MOPC-315-associated Ags. Finally, we have previously shown that TCR V beta 8+/CD8+ T cells are involved in the curative effectiveness of low dose L-PAM for mice bearing a large MOPC-315 tumor. Here we show that TNF is important for the ability of MOPC-315-specific V beta 8+/CD8+ T cell lines from L-PAM TuB mice to bring about tumor eradication upon adoptive transfer into tumor-bearing mice. Taken together, these studies illustrate that low dose L-PAM mediates its therapeutic effectiveness for mice bearing a large MOPC-315 tumor, at least in part, via TNF production (e.g., by V beta 8+/CD8+ T cells), which in turn promotes the generation of anti-MOPC-315 CTL activity.