Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype

Purpose: Tumor-specific T cells are frequently induced naturally in melanoma patients and infiltrate tumors. It is enigmatic why these patients fail to experience tumor regression. Given that CD8(+) T cells mediate antigen-specific killing of tumor cells, the focus of this study was to identify alterations in the differentiation of CD8(+) residing at the tumor site, with emphasis on a population expressing CD57, a marker for terminal differentiation. Experimental Design: We conducted flow cytometric analysis of CD8(+) tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases with known T-cell differentiation markers. For comparison, peripheral blood mononuclear cells were isolated from matched melanoma patients. We sorted different CD8(+) subsets found in TIL and determined their effector functions. In addition, we carried out V beta clonotype expression analysis of T-cell receptors to determine lineage relationship between the CD8(+) TIL subsets. Results: The majority of CD8(+) TIL was in the early-effector memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells coexpressing CD27, CD28, CD57, and Granzyme B, with little or no perforin. These cells could be induced to proliferate, produce a high level of IFN-gamma, and differentiate into CD27(-)CD57(+), perforin(high) mature CTL in vitro. Addition of TGF-beta 1 prevented further differentiation. Conclusions: Our studies identified a novel subset of incompletely differentiated CD8(+) CTL coexpressing early effector memory and late CTL markers. This population resembles that found in patients with uncontrolled chronic viral infections. TGF-beta 1, frequently produced by melanoma tumors, may be a key cytokine inhibiting further maturation of this subset. Clin Cancer Res; 18(9); 2465-77. (C) 2012 AACR.