A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumor-specific immune response

In a significant proportion of melanoma patients, CTL specific for the mela n-A(26/7-35) epitope can be detected in peripheral blood using HLA-A2/pepti de tetramers, However, the functional capacity of these CTL has been contro versial, since although they prove to be effective killers after in vitro e xpansion, in some patients they have blunted activation responses ex vivo. We used phenotypic markers to characterize melan-A tetramer(+) cells in bot h normal individuals and melanoma patients, and correlated these markers wi th ex vivo assays of CTL function. Melanoma patients with detectable melan- A tetramer(+). cells in peripheral blood fell into two groups. Seven of thi rteen patients had a CCR7(+) CD45R0(-) CD45RA(+) phenotype, the same as tha t found in some healthy controls, and this phenotype was associated with a lack of response to melan-A peptide ex vivo. In the remaining six patients, melan-A tetramer+ cells were shifted toward a CCR7(-) CD45R0(+) CD45RA(-) phenotype, and responses to melan-A peptide could be readily demonstrated e x vivo. When lymph nodes infiltrated by melan-A-expressing melanoma cells w ere examined, a similar dichotomy emerged. These findings demonstrate that activation of melan-A-specific CTL occurs in only some patients with malign ant melanoma, and that only patients with such active immune responses are capable of responding to Ag in ex vivo assays.