Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
| Autor: | Noelle V. Frey, F. Brad Johnson, David L. Porter, Gregory L. Beatty, Robert H. Vonderheide, Theresa A. Colligon, Barbara A. Vance, Ran Reshef, Jasmine S. Smith, Kunal P. Patel |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Cancer Research Myeloid medicine.medical_treatment Programmed Cell Death 1 Receptor Graft vs Leukemia Effect Hematopoietic stem cell transplantation CD8-Positive T-Lymphocytes Biology Article Interferon-gamma Young Adult Myelogenous Antigens CD Lysosomal-Associated Membrane Protein 1 Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Humans Cytotoxic T cell Cellular Senescence Aged Myeloid leukemia Middle Aged Telomere medicine.disease Leukemia Myeloid Acute Leukemia surgical procedures operative medicine.anatomical_structure Oncology Immunology Cancer research Female Apoptosis Regulatory Proteins CD8 Stem Cell Transplantation Chronic myelogenous leukemia |
| Zdroj: | Clinical Cancer Research. 15:4944-4953 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: 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.Experimental Design: 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|