Functional unresponsiveness and replicative senescence of myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation.
OBJECTIVE
The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8(+) T-cell responses to MHC class I-restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood.


METHODS
We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8(+) T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library.


RESULTS
Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8(+) T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8(+) T cells from patients were predominantly CD28(-) CD57(+) and had relatively short telomeres, consistent with cellular senescence.


CONCLUSIONS
Circulating leukemia-specific CD8(+) T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.
Beatty
Gregory L
GL
Abramson Family Cancer Research Institute, Abramson Cancer Center, Department of Pathology and Laboratory Medicine, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Smith
Jasmine S
JS
Reshef
Ran
R
Patel
Kunal P
KP
Colligon
Theresa A
TA
Vance
Barbara A
BA
Frey
Noelle V
NV
Johnson
F Brad
FB
Porter
David L
DL
Vonderheide
Robert H
RH
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016922:Cellular Senescence / Q000276:immunology*; D005260:Female; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000601:surgery*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000601:surgery*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D033581:Stem Cell Transplantation; D016615:Telomere / Q000276:immunology; D055815:Young Adult
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D052118:Lysosomal-Associated Membrane Protein 1; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma