Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients

We identified circulating CD8(+) T-cell populations specific for the tumor- associated antigens (TAAs) MART-1 (27-35) or tyrosinase (368-376) in six of eleven patients with metastatic melanoma using peptide/HLA-A*0201 tetramer s. These TAA-specific populations were of two phenotypically distinct types : one, typical for memory/effector T cells; the other, a previously undescr ibed phenotype expressing both naive and effector cell markers. This latter type represented more than 2% of the total CD8(+) T cells in one patient, permitting detailed phenotypic and functional analysis. Although these cell s have many of the hallmarks of effector T cells, they were functionally un responsive, unable to directly lyse melanoma target cells or produce cytoki nes in response to mitogens. In contrast, CD8(+) T cells from the same pati ent were able to lyse EBV-pulsed target cells and showed robust allogeneic responses. Thus, the clonally expanded TAA-specific population seems to hav e been selectively rendered anergic in vivo. Peptide stimulation of the TAA -specific T-cell populations in other patients failed to induce substantial upregulation of CD69 expression, indicating that these cells may also have functional defects, leading to blunted activation responses. These data de monstrate that systemic TAA-specific T-cell responses can develop de novo i n cancer patients, but that antigen-specific unresponsiveness may explain w hy such cells are unable to control tumor growth.