TNF plays an essential role in tumor regression after adoptive transfer of perforin/IFN-γ double knockout effector T cells

We have recently shown that effector T cells (T-E) lacking either perforin or IFN-gamma are highly effective mediators of tumor regression. To rule out compensation by either mechanism, TE deficient in both perforin and IFN-gamma (perforin knockout (PKO)/IFN-gamma knockout (GKO)) were generated. The adoptive transfer of PKO/GKO T, mediated complete tumor regression and cured wild-type animals with established pulmonary metastases of the B16BL6-D5 (D5) melanoma cell line. PKO/GKO T-E also mediated tumor regression in D5 tumor-bearing PKO, GKO, or PKO/GKO recipients, although in PKO/GKO recipients efficacy was reduced. PKO/GKO T-E exhibited tumor-specific TNF-alpha production and cytotoxicity in a 24-h assay, which was blocked by the soluble TNFRII-human IgG fusion protein (TNFRII:Fc). Blocking TNF in vivo by administering soluble TNFR 11 fusion protein (TNFRII:Fc) significantly reduced the therapeutic efficacy of PKO/GKO, but not wild-type T-E. This study identifies perforin, IFN-gamma and TNF as a critical triad of effector molecules that characterize therapeutic antitumor T cells. These insights could be used to monitor and potentially tune the immune response to cancer vaccines.