Anti-tumor activity of cytotoxic T lymphocytes elicited with recombinant and synthetic forms of a model tumor-associated antigen

J Immunother Emphasis Tumor Immunol. 1995 Oct;18(3):139-46. doi: 10.1097/00002371-199510000-00001.

Abstract

The recent cloning of tumor-associated antigens (TAAs) recognized by CD8+ T lymphocytes (TCD8+) has made it possible to use recombinant and synthetic forms of TAAs to generate TCD8+ with anti-tumor activity. To explore new therapeutic strategies in a mouse model, we retrovirally transduced the experimental murine tumor CT26(H-2d), with the lacZ gene encoding our model TAA, beta-galactosidase (beta-gal). The transduced cell line, CT26.CL25, grew as rapidly and as lethally as the parental cell line in normal, immunocompetent animals. In an attempt to elicit TCD8+ directed against our model TAA by using purely recombinant and synthetic forms of our model TAA, we synthesized a nine-amino-acid long immunodominant peptide of beta-gal (TPH-PARIGL), corresponding to amino acid residues 876-884, which was known to be presented by the Ld major histocompatibility complex (MHC) class I molecule, and a recombinant vaccinia virus encoding the full-length beta-gal protein (VJS6). Splenocytes obtained from naïve mice and co-cultured with beta-gal peptide could not be expanded in primary ex vivo cultures. However, mice immunized with VJS6, but not with a control recombinant vaccinia virus, yielded splenocytes that were capable of specifically lysing CT26.CL25 in vitro after co-culture with beta-gal peptide. Most significantly, adoptive transfer of these cells could effectively treat mice bearing 3-day-old established pulmonary metastases. These observations show that therapeutic TCD8+ directed against a model TAA could be generated by using purely recombinant and synthetic forms of this antigen. These findings point the way to a potentially useful immunotherapeutic strategy, which has been made possible by the recent cloning of immunogenic TAAs that are expressed by human malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm* / genetics
  • Female
  • Humans
  • Immunodominant Epitopes / genetics
  • Immunotherapy, Adoptive
  • Lac Operon
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis
  • Oligopeptides / genetics
  • Oligopeptides / immunology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transduction, Genetic
  • Tumor Cells, Cultured
  • beta-Galactosidase / chemical synthesis
  • beta-Galactosidase / genetics

Substances

  • Antigens, Neoplasm
  • Immunodominant Epitopes
  • Oligopeptides
  • Recombinant Proteins
  • beta-Galactosidase