TNF plays an essential role in tumor regression after adoptive transfer of perforin/IFN-gamma 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, 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.
Poehlein
Christian H
CH
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.
Hu
Hong-Ming
HM
Yamada
Jane
J
Assmann
Ilka
I
Alvord
W Gregory
WG
Urba
Walter J
WJ
Fox
Bernard A
BA
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*
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