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TNF Plays an Essential Role in Tumor Regression after Adoptive Transfer of Perforin/IFN- Double Knockout Effector T Cells ¹

Christian H. Poehlein^*, Hong-Ming Hu^*,, Jane Yamada^*, Ilka Assmann^*, W. Gregory Alvord^||, Walter J. Urba^,¶ and Bernard A. Fox^2,*,,,,¶

Laboratories of ^* Molecular and Tumor Immunology and Clinical Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213; Departments of Biochemistry and Molecular Biology, Oregon Graduate Institute, and Molecular Microbiology and Immunology, and ^¶ Oregon Cancer Center, Oregon Health and Science University, Portland, OR 97202; and ^|| Data Management Services, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702

We have recently shown that effector T cells (T_E) lacking either perforin or IFN- are highly effective mediators of tumor regression. To rule out compensation by either mechanism, T_E deficient in both perforin and IFN- (perforin knockout (PKO)/IFN- knockout (GKO)) were generated. The adoptive transfer of PKO/GKO T_E 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- 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 II fusion protein (TNFRII:Fc) significantly reduced the therapeutic efficacy of PKO/GKO, but not wild-type T_E. This study identifies perforin, IFN-, 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.

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