title: Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy.
abstract: In humans, the pathways of memory T-cell differentiation remain poorly defined. Recently, adoptive cell transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen-specific CD8+ T cells during their transition from in vitro cultured effector cells to long-term persistent memory cells following ACT to 6 responding patients. Tumor-reactive T cells used for therapy were generally late-stage effector cells with a CD27Lo CD28Lo CD45RA- CD62 ligand- (CD62L-) CC chemokine receptor 7- (CCR7-) interleukin-7 receptor alphaLo (IL-7RalphaLo) phenotype. After transfer, rapid up-regulation and continued expression of IL-7Ralpha in vivo suggested an important role for IL-7R in immediate and long-term T-cell survival. Although the tumor antigen-specific T-cell population contracted between 1 and 4 weeks after transfer, stable numbers of CD27+)CD28+ tumor-reactive T cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T cells in vivo. At 2 months after transfer, melanoma-reactive T cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L- CCR7- profile, which may explain in part their ability to mediate tumor destruction.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010641:Phenotype; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D020395:Receptors, Interleukin-7; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C415350:interleukin-7 receptor, alpha chain