title: Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity.
abstract: The efficacy of immune surveillance and antigen-specific cancer immunotherapy equally depends on the activation of a sustained immune response targeting cancer antigens and the susceptibility of cancer cells to immune effector mechanisms. Using functional expression cloning and T-cell receptor (TCR) transgenic mice, we have identified cyclooxygenase 2/prostaglandin-endoperoxide synthase 2 (COX-2) as resistance factor against the cytotoxicity induced by activated, antigen-specific T cells. Expressing COX-2, but not a catalytically inactive COX-2 mutant, increased the clonogenic survival of E1A-transformed murine cancer cells when cocultured with lymphocytes from St42Rag2(-/-) mice harboring a transgenic TCR directed against an E1A epitope. COX-2 expressing tumors established in immune-deficient mice were less susceptible to adoptive immunotherapy with TCR transgenic lymphocytes in vivo. Also, immune surveillance of COX-2-positive tumor cells in TCR transgenic mice was less efficient. The growth of murine MC-GP tumors, which show high endogenous COX-2 expression, in immunocompetent mice was effectively suppressed by treatment with a selective COX-2 inhibitor, celecoxib. Mechanistically, COX-2 expression blunted the interferon-gamma release of antigen-specific T cells exposed to their respective cellular targets, and increased the expression of interleukin-4 and indoleamine 2,3-dioxygenase by tumor cells. Addition of interferon-gamma sensitized COX-2 expressing cancer cells to tumor suppression by antigen-specific T cells. In conclusion, COX-2, which is frequently induced in colorectal cancer, contributes to immune evasion and resistance to antigen-specific cancer immunotherapy by local suppression of T-cell effector functions.
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Göbel
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Breitenbuecher
authors.affiliation: 1] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany [2] Department of Immunology, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kalkavan
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: P S
authors.initials: PS
authors.lastname: Hähnel
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hoffarth
authors.affiliation: Department of Immunology, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Merches
authors.affiliation: Institute for Immunology, University Medical Center, Mainz 55101, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schild
authors.affiliation: Department of Immunology, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: K S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: 1] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schuler
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013045:Species Specificity
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma; D051546:Cyclooxygenase 2