Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.
Mutated p21 ras proteins (muRas) are present in approximately 90% of pancreatic adenocarcinomas and express mutants which can function as cancer-specific antigens. To evaluate the frequency and magnitude of the natural T-cell response against muRas in 19 HLA-A2-positive patients with muRas-positive pancreatic carcinomas, antigen-experienced T lymphocytes in fresh peripheral blood mononuclear cells were shown by IFN-gamma enzyme-linked immunospot using muRas peptides (5-21) that encompass both HLA class I (HLA-A2)- and class II-restricted (HLA-DRB1) epitopes. Six of 19 patients (32%) were found to have a specific T-cell response against individual mutation-specific ras(5-21) but not against other ras mutations or wild-type ras. In contrast, none of 19 healthy subjects had T cells specifically secreting IFN-gamma (P = 0.004). The T-cell response consisted of both CD8(+) and CD4(+) T cells but was dominated by CD8 T cells in three of four patients. MuRas(5-14) and muRas(6-14) were shown to specifically induce CD8(+) T-cell mediated cytotoxicity against HLA-A2-positive, muRas-bearing pancreatic carcinoma cells. The T-cell response was not correlated with prognostic or clinical variables such as tumor-node-metastasis status, stage, or survival. In conclusion, a natural T-cell response against muRas proteins that could be exploited for immunostimulatory therapeutic approaches has been shown in a significant proportion of patients with pancreatic cancer.
Department of Internal Medicine I , University of Saarland Medical School, Homburg/Saar, Germany.
Boris
B
Kubuschok
Frank
F
Neumann
Rainer
R
Breit
Martina
M
Sester
Claudia
C
Schormann
Claudia
C
Wagner
Urban
U
Sester
Frank
F
Hartmann
Mathias
M
Wagner
Klaus
K
Remberger
Martin
M
Schilling
Michael
M
Pfreundschuh
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000276:immunology; D015689:Oncogene Protein p21(ras) / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D014764:Viral Proteins; D015689:Oncogene Protein p21(ras)