Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses

Eur J Immunol. 1999 Dec;29(12):3867-76. doi: 10.1002/(SICI)1521-4141(199912)29:12<3867::AID-IMMU3867>3.0.CO;2-E.

Abstract

The lymphocyte activation gene-3 (LAG-3) product is an MHC class II ligand related to CD4. We investigated whether LAG-3 could be used in vivo to stimulate MHC class II(+) antigen-presenting cells (APC), such as resident macrophages or dendritic cells known to play a crucial role in processing and presenting of antigens to the immune system. We first introduced human (h) LAG-3 or mouse LAG-3 into three types of tumor cells (MCA 205, TS / A and RENCA) to evaluate its capacity to stimulate a tumor-specific immune response in vivo. In contrast to the progressive growth of wild-type cells in syngeneic mice, LAG-3-transfected tumors completely regressed or their growth was markedly reduced. Mice were significantly to completely protected against a rechallenge with parental tumor cells. Protection induced by hLAG-3(+) tumor cells involved recruitment of a CD8(+) T cell response since nu / nu mice and CD8-depleted mice did not reject tumors, and a systemic tumor-specific CTL activity was induced. Co-administration of soluble LAG-3 with wild-type tumor cells also markedly reduced primary tumor growth. Interestingly, immunization with LAG-3(+) tumor cells or co-administration of soluble LAG-3 with irradiated wild-type tumor cells reduced the growth of pre-established tumors. We therefore suggest that LAG-3 could be used as a vaccine adjuvant for its ability to trigger APC via MHC class II molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation* / genetics
  • Antigen Presentation* / immunology
  • Antigens, CD*
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Cell Communication / immunology
  • Cytotoxicity, Immunologic* / genetics
  • Dendritic Cells / immunology
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Macrophages / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • Membrane Proteins
  • Lymphocyte Activation Gene 3 Protein