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

Abstract

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 performed flow cytometric analysis of CD8+ tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases using known T-cell differentiation markers. For comparison, PBMC were isolated from matched melanoma patients. We sorted different CD8+ subsets found in TIL and determined their effector functions. In addition, we performed Vβ spectratyping of T-cell receptors to determine lineage relationship between the CD8+ TIL subsets. RESULTS The majority of CD8+ TIL were in the early effector-memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells co-expressing early effector-memory markers and end-stage CTL marker, CD57, yet having low to absent perforin expression. These cells could be induced to proliferate, produce a high level of IFN-γ, and differentiate into CD27−CD57+, perforinhigh mature CTL in vitro. Addition of TGF-β1 prevented this further differentiation. CONCLUSIONS Our studies identified a novel subset of incompletely differentiated CD8+ CTL co-expressing early effector-memory and late CTL markers. This population resembles that found by in patients with uncontrolled chronic viral infections. TGF-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting the further maturation of this subset.

PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

“…Upregulation of CD57 is normally interpreted as continued progression to a terminally differentiated phenotype (30). The population of CD27 þ CD57 þ cells that we described here is unusual but has been described previously in patients with melanoma (31).…”

Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57

“…From these experiments, we concluded that CD57 upregulation on the CAR T cells upon encounter with the GBM-SCs did not reflect a terminally differentiated T cell state. CD57 upregulation on CD27+ T cells has recently been linked to a state of incomplete differentiation of tumor-infiltrating T cells (TILs), which, in contrast to terminally differentiated T cells, are still able to proliferate upon TCR stimulation but rapidly undergo terminal differentiation (indicated by the downregulation of CD27 and CD28 and the upregulation of perforin) upon further antigen stimulation [ 33 ]. After incubation with NCH421k GBM-SCs and subsequent upregulation of CD57, our AC133-specific CAR T cells still proliferated when further cultured on anti-CD3 antibody-coated plates or with AC133+ NCH421k GBM-SCs for several days and they downregulated neither CD27 nor CD28 (data not shown), suggesting that the strong CD57 upregulation on the CAR T cells upon incubation with GBM-SCs did not reflect terminal replicative senescence, nor was it identical to the state of incomplete T cell differentiation recently described by Wu et al .…”

Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells

“…Wu et al . [14] recently described a subpopulation of melanoma-specific CD8+ tumor-infiltrating lymphocytes (TILs) with hybrid phenotypic and functional properties of both an early effector-memory cell and a terminally differentiated effector cell co-expressing CD27, CD28, and CD57. These CD57+ T cells were classified as incompletely differentiated T cells.…”