Differential loss of T cell signaling molecules in metastatic melanoma patients' T lymphocyte subsets expressing distinct TCR variable regions

In this study we tested the hypothesis that loss of T cell signaling molecu les in metastatic melanoma patients' T cells may affect differently T cell subsets characterized by distinct TCR variable regions. By a two-color immu nofluorescence technique, expression of xi-chain, Ick, and ZAP-70 was evalu ated in CD3(+) T cells and in three representative T cell subsets expressin g TCRAV2, TCRBVZ, or TCRBV18, Partial loss of Ick and ZAP-70 was found in C D3+ T cells from PBL of most melanoma patients, but not of healthy donors. The extent of xi-chain, Ick, and ZAP-70 loss depended on the TCRV region ex pressed by the T cells, and this association was maintained or increased du ring progression of disease. Coculture of patients' or donors' T cell with melanoma cells, or with their supernatants, but not with normal fibroblasts or their supernatants, down-modulated expression of xi-chain, Ick, and ZAP -70 in a TCRV region-dependent way, Immunodepletion of soluble HLA class I molecules present in tumor supernatants, but not of soluble ICAM-1, blocked the suppressive effect on T cell signaling molecule expression. T cell act ivation with mAbs to a single TCRV region and to CD28 led to significant an d TCRV region-specific re-induction of xi-chain expression. These findings indicate that extent of TCR signaling molecules loss in T lymphocytes from metastatic melanoma patients depends on the TCRV region and suggest that tu mor-derived HLA class I molecules may contribute to induce such alterations .