Selective responsiveness to common gamma chain cytokines in peripheral blood-derived cytotoxic T lymphocytes induced by Melan-A/MART-1(27-35)targeted active specific immunotherapy.
We have comparatively evaluated the proliferative response of CTL induced in metastatic melanoma patients upon immunization against Melan-A/MART-1(27-35) tumor associated antigen (TAA) to IL-2, IL-7 or IL-15 cytokines, sharing a receptor common gamma-chain (c gamma-c cytokines). Twenty-eight CTL clones were generated from CD8+ T cells obtained from 3 patients during the contraction phase of immune response following a successful vaccine mediated expansion of specific effectors. All clones were able to kill tumor cell lines expressing HLA-A0201 and Melan-A/MART-1, and displayed phenotypic characteristics of effector/memory (CD45RA-/CCR7-) or CD45RA+/CCR7- effector cells in intermediate to late developmental stage (CD28-/CD276+/-) CTL. Proliferative responses could be elicited or enhanced by IL-2 and IL-15, but not IL-7, in the absence or in the presence of T-cell receptor (TCR) triggering, respectively. Accordingly, only IL-2 and IL-15 were able to promote the survival of the CTL clones under investigation. While all clones expressed high amounts of receptor c gamma-c (CD132), lower, but detectable, expression of IL-7 receptor alpha chain was also observed. CD8+ cells from one of the patients treated were obtained 6 months after the last vaccine boost and were cultured in the presence of Melan-A/MART-1(27-35) and each of the 3 cytokines under investigation. Consistent with data from CTL clones, expansion of Melan-A/MART-1(27-35) tetramer positive cells was only observed in the presence of IL-2 or IL-15 but not IL-7. Instead, when CD8+ cells from the same patient were sampled shortly (14 days) after an additional vaccination only IL-2 was able to promote the expansion of Melan-A/MART-1(27-35) tetramer positive cells. Taken together these data suggest a selective responsiveness of TAA-specific CTL to different c gamma-c cytokines.
von Holzen
Urs
U
Institut für Chirurgische Forschung und Spitalmanagement and Department Forschung, University of Basel, Switzerland.
Adamina
Michel
M
Bolli
Martin
M
Weber
Walter P
WP
Zajac
Paul
P
Groeper
Celia
C
Reschner
Anca
A
Feder
Chantal
C
Schumacher
Reto
R
Marti
Walter
W
Oertli
Daniel
D
Heberer
Michael
M
Spagnoli
Giulio C
GC
D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy; D009363:Neoplasm Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7