High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival

We have identified an antigen recognized by autologous CTL on the lung carc inoma cells of a patient who enjoyed a favorable clinical evolution, being alive 10 years after partial resection of the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts mala te to pyruvate, In the tumor cell lint derived from the patient, only the m utated malic enzyme allele is expressed, because of a loss of heterozygosit y in the region of chromosome 6 that contains this locus, Tetramers of solu ble HLA-A2 molecules loaded with the antigenic peptide stained similar to0. 4% of the patient's blood CD8 T cells. When these cells were stimulated in clonal conditions, 25% of them proliferated, and the resulting clones were lytic and specific for the mutated malic enzyme peptide, T-cell receptor an alysis indicated that almost all of these antimalic CTLs shared the same re ceptor. Antimalic T cells Here consistently found in blood samples collecte d from the patient between 1990 and 1999, at frequencies ranging from 0.1 t o 0.4% of the CD8 cells. Their frequency appeared to double within 2 weeks after intradermal inoculation of lethally irradiated autologous tumor cells . These results indicate that nonmelanoma cancer patients may also have a h igh frequency of blood CTLs directed against a tumor-specific antigen.