Detection and characterization of a novel subset of CD8⁺CD57⁺ T cells in metastatic melanoma with an incompletely differentiated phenotype.
OBJECTIVE
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.


METHODS
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 Vβ 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-γ, and differentiate into CD27(-)CD57(+), perforin(high) mature CTL in vitro. Addition of TGF-β1 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-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting further maturation of this subset.
Department of Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Richard C
RC
Wu
Shujuan
S
Liu
Jessica A
JA
Chacon
Sheng
S
Wu
Yufeng
Y
Li
Pariya
P
Sukhumalchandra
James L
JL
Murray
Jeffrey J
JJ
Molldrem
Patrick
P
Hwu
Hanspeter
H
Pircher
Gregory
G
Lizée
Laszlo G
LG
Radvanyi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018959:CD57 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000556:secondary*; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D055815:Young Adult
D018959:CD57 Antigens; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7