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

Abstract

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 tetramers. These TAA-specific populations were of two phenotypically distinct types: one, typical for memory/effector T cells; the other, a previously undescribed 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 cells have many of the hallmarks of effector T cells, they were functionally unresponsive, unable to directly lyse melanoma target cells or produce cytokines in response to mitogens. In contrast, CD8+ T cells from the same patient were able to lyse EBV-pulsed target cells and showed robust allogeneic responses. Thus, the clonally expanded TAA-specific population seems to have 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 demonstrate that systemic TAA-specific T-cell responses can develop de novo in cancer patients, but that antigen-specific unresponsiveness may explain why such cells are unable to control tumor growth.

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

“…These cell frequency data fit in well with our previous analyses of other HLA-A*0201 melanoma and vitiligo patients [13,14] and are in agreement with the estimates reported in the literature [5,8,9]. The in vivo priming and functional capacity of melanocyte-specific lymphocytes are important issues, since recent data suggested that Melan-Aspecific cells circulating in some melanoma patients are either ignorant (not primed) or anergic [8,23,24]. By complementing the use of A2/Melan-A tetramers with both intracellular perforin staining and surface staining of memory/naivety markers, we found that the percentages of activated cells were also comparable.…”

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

“…Recent data from our laboratory and other laboratories indicate that tumour-infiltrating and peripheral T cells of many patients with cancer are primed for apoptosis (Rabinowich et al, 1998;Reichert et al, 1998b;Lee et al, 1999;Reichert et al, 2002;, and that the death of effector T cells could be responsible for inadequate antitumour functions. We previously reported that relative to healthy normal controls (NC), patients with cancer have increased proportions of circulating T cells that bind Annexin V (Dworacki et al, 2001;Hoffmann et al, 2002).…”

Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice

“…13,14 T cells that recognize TAAs are present in the blood of cancer patients. [15][16][17] However, development of antitumor immunity is inhibited by peripheral tolerance and immunosuppression due to cytokines secreted by tumors. 17,18 Furthermore, cancer cells use various methods to escape recognition and killing by T cells.…”