Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma

Int Immunopharmacol. 2017 Mar:44:197-202. doi: 10.1016/j.intimp.2017.01.014. Epub 2017 Jan 19.

Abstract

Hypoxic tumor microenvironment makes cancer cells to be therapy-resistant and hypoxia-inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often associated with von Hippel-Lindau (VHL) gene mutations, leading to up-regulation of HIFs. However, from a different point of view, this suggests the possibility that HIFs could be promising targets in anti-cancer therapy. In this study, we searched for HIF-1α-derived peptides that are able to induce RCC-reactive cytotoxic T lymphocytes (CTLs) from HLA-A24+ RCC patients. Among five peptides derived from HIF-1α, which were prepared based on the binding motif to the HLA-A24 allele, a HIF-1α278-287 peptide induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24+ RCC patients most effectively. In immunoblot assays, the expression of HIF-1α was lowly detected in whole and nuclear lysates of RCC cell lines even under normoxia (20% O2), and their expression in whole lysates was increased under hypoxia (1% O2). Additionally, HIF-1α278-287 peptide-stimulated T cells showed a higher cytotoxicity against HLA-A24+ HIF-1α-expressing RCC cells than against HLA-A24- HIF-1α-expressing RCC cells. The cytotoxicity was inhibited by the addition of HIF-1α278-287 peptide-pulsed cold target cells. Altogether, these results indicate that the HIF-1α278-287 peptide could be a candidate for peptide-based anti-cancer vaccines for HLA-A24+ RCC patients.

Keywords: CTL; HIF-1α; HLA-A24; Peptide; Renal cell carcinoma.

MeSH terms

  • Cancer Vaccines / immunology*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / therapy*
  • Cells, Cultured
  • HLA-A24 Antigen / metabolism
  • Humans
  • Hypoxia / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology*
  • Immunotherapy, Adoptive / methods*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / therapy*
  • Lymphocyte Activation
  • Peptide Fragments / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / transplantation
  • Tumor Microenvironment
  • Vaccines, Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • Cancer Vaccines
  • HIF1A protein, human
  • HLA-A24 Antigen
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Peptide Fragments
  • Vaccines, Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human