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

• Published in: The Journal of immunology (1950) Vol. 170; no. 4; pp. 2004 - 2013
• Main Authors: Poehlein, Christian H, Hu, Hong-Ming, Yamada, Jane, Assmann, Ilka, Alvord, W Gregory, Urba, Walter J, Fox, Bernard A
• Format: Journal Article
• Language: English
• Published: United States 15-02-2003
• Subjects: Adoptive Transfer - methods; Animals; Antigens, CD - administration & dosage; Antigens, CD - immunology; Antigens, CD - metabolism; Binding, Competitive - genetics; Binding, Competitive - immunology; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; Cells, Cultured; Cytotoxicity, Immunologic - genetics; Epitopes, T-Lymphocyte - immunology; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - metabolism; Injections, Intraperitoneal; Injections, Subcutaneous; Interferon-gamma - deficiency; Interferon-gamma - genetics; Lung Neoplasms - immunology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Perforin; Pore Forming Cytotoxic Proteins; Receptors, Tumor Necrosis Factor - administration & dosage; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Type II; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - transplantation; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - transplantation; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.4.2004

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, T(E) deficient in both perforin and IFN-gamma (perforin knockout (PKO)/IFN-gamma 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-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 II 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.