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Naturally Occurring T-Cell Response against Mutated p21 Ras Oncoprotein in Pancreatic Cancer

Authors' Affiliations: ¹ Department of Internal Medicine I and ² IV, ³ Department of Surgery, and ⁴ Institute of Pathology, University of Saarland Medical School, Homburg/Saar, Germany

Requests for reprints: Michael Pfreundschuh, Medizinische Klinik I, Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany. Phone: 49-6841-162-3002; Fax: 49-6841-162-3101; E-mail: inmpfr{at}uniklinikum-saarland.de.

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- 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- (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.