title: Engagement of the OX-40 receptor in vivo enhances antitumor immunity.
abstract: The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20-55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA. weinbera@ohsu.edu
authors.forename: A D
authors.initials: AD
authors.lastname: Weinberg
authors.forename: M M
authors.initials: MM
authors.lastname: Rivera
authors.forename: R
authors.initials: R
authors.lastname: Prell
authors.forename: A
authors.initials: A
authors.lastname: Morris
authors.forename: T
authors.initials: T
authors.lastname: Ramstad
authors.forename: J T
authors.initials: JT
authors.lastname: Vetto
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: G
authors.initials: G
authors.lastname: Alvord
authors.forename: C
authors.initials: C
authors.lastname: Bunce
authors.forename: J
authors.initials: J
authors.lastname: Shields
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000517:prevention & control; D005260:Female; D006801:Humans; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D012513:Sarcoma, Experimental / Q000276:immunology / Q000517:prevention & control; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008024:Ligands; D011971:Receptors, Immunologic; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C505717:Tnfrsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7