Possible role of arginase-1 in concomitant tumor immunity

PLoS One. 2014 Mar 10;9(3):e91370. doi: 10.1371/journal.pone.0091370. eCollection 2014.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenovirus E1A Proteins / metabolism
  • Animals
  • Arginase / metabolism*
  • CD3 Complex / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / pathology
  • Cytotoxicity, Immunologic
  • Immunity*
  • Immunization
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Neoplasms / enzymology*
  • Neoplasms / immunology*
  • Ovalbumin / immunology
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / immunology
  • Transfection


  • Adenovirus E1A Proteins
  • CD3 Complex
  • Recombinant Fusion Proteins
  • Ovalbumin
  • Arginase