title: Possible role of arginase-1 in concomitant tumor immunity.
abstract: The expression of Adenovirus serotype 2 or serotype 5 (Ad2/5) E1A in tumor cells reduces their tumorigenicity in vivo by enhancing the NK cell mediated and T cell mediated anti-tumor immune response, an activity that correlates with the ability of E1A to bind p300. We determined if E1A could be used as a molecular adjuvant to enhance antigen-specific T cell responses to a model tumor antigen, ovalbumin (OVA). To achieve this goal, we stably expressed a fusion protein of E1A and OVA (MCA-205-E1A-OVA), OVA (MCA-205-OVA) or a mutant version of E1A unable to bind p300 and OVA (E1A-Δp300-OVA) in the B6-derived, highly tumorigenic MCA-205 tumor cell line. MCA-205-E1A-OVA tumor cells were over 10,000 fold less tumorigenic than MCA-205-OVA, MCA-205-E1A-Δp300-OVA, or MCA-205 in B6 mice. However, immunization of B6 mice with live MCA-205-OVA, MCA-205-E1A-Δp300-OVA and MCA-E1A-OVA tumor cells induced nearly equivalent OVA-specific CD4 T cells and CD8 CTL responses. Further studies revealed that mice with primary, enlarging MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumors on one flank exhibited OVA-specific anti-tumor T cell responses that rejected a tumorigenic dose of MCA-205-OVA cells on the contralateral flank (concomitant tumor immunity). Next we found that tumor associated macrophages (TAMs) in progressive MCA-205-OVA tumors, but not MCA-205-E1A-OVA tumors that expressed high levels of arginase-1, which is known to have local immunosuppressive activities. In summary, immunization of mice with MCA-205 cells expressing OVA, E1A-Δp300-OVA or E1A-OVA induced equivalent OVA-specific CD4 and CD8 anti-tumor responses. TAMs found in MCA-205-OVA, but not MCA-205-E1A-OVA, tumors expressed high levels of arginase-1. We hypothesize that the production of arginase-1 by TAMs in MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumor cells leads to an ineffective anti-tumor immune response in the tumor microenvironment, but does not result in inhibition of a systemic anti-tumor immunity.
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Children's Research Institute, Milwaukee, Wisconsin, United States of America; Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Korrer
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 2 Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 3 Children's Research Institute, Milwaukee, Wisconsin, United States of America; 4 Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 5 Department of Microbiology and Immunology, University of Louisville, Louisville, United States of America.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Children's Research Institute, Milwaukee, Wisconsin, United States of America; Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Routes
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D063646:Carcinogenesis / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D007109:Immunity; D007114:Immunization; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D014162:Transfection
chemical_list: D017500:Adenovirus E1A Proteins; D017252:CD3 Complex; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin; D001119:Arginase