A P16(INK4A)-INSENSITIVE CDK4 MUTANT TARGETED BY CYTOLYTIC T-LYMPHOCYTES IN A HUMAN-MELANOMA

A mutated cyclin-dependent kinase 4 (CDK4) was identified as a tumor-s pecific antigen recognized by HL4-A2.1-restricted autologous cytolytic T lymphocytes (CTLs) in a human melanoma. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patient's lymphocytes. The mutation, an arginine-to-cys teine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16(INK4a), but no t of p21 or of p27(KIP1). The same mutation was found in one additiona l melanoma among 28 melanomas analyzed. These results suggest that mut ation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16(INK4a).