Naturally occurring T-cell response against mutated p21 Ras oncoprotein in pancreatic cancer

Abstract

Mutated p21 ras proteins (muRas) are present in ∼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-γ 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 ras5-21 but not against other ras mutations or wild-type ras. In contrast, none of 19 healthy subjects had T cells specifically secreting IFN-γ (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. MuRas5-14 and muRas6-14 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. © 2006 American Association for Cancer Research.