title: TNF plays an essential role in tumor regression after adoptive transfer of perforin/IFN-gamma double knockout effector T cells.
abstract: 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.
authors.affiliation: Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR 97213, USA.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Poehlein
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hu
authors.forename: Jane
authors.initials: J
authors.lastname: Yamada
authors.forename: Ilka
authors.initials: I
authors.lastname: Assmann
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D007141:Immunoglobulin Fc Fragments; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma