Therapeutic effectiveness of recombinant cancer vaccines is associated with a prevalent T-cell receptor alpha usage by melanoma-specific CD8+ T lymphocytes.
Definition of immune variables that correlate with the antitumor activity of cancer vaccines is critical for monitoring immunotherapy protocols. To define surrogate end points predictive of the therapeutic efficacy of recombinant vaccines based on melanoma antigen tyrosinase-related protein (TRP)-2, we evaluated several properties of antigen-specific CD8(+) T lymphocytes in single mice undergoing either prophylactic or therapeutic immunization. Predictive markers for the efficacy of genetic vaccination were identified in the prophylactic model used. Interestingly, the number of tetramer(+) CD8(+) T lymphocytes expanded in vitro after a single cycle of stimulation with the immunodominant TRP-2 peptide was of the highest predictive value. In the therapeutic model, no variable examined at a single mouse level predicted the long-term therapeutic effect. Mice that survived did not show the highest expansion of antigen-specific lymphocytes or the more functionally active effectors, ex vivo or after in vitro culture with the peptide antigen. Successful therapy correlated strictly with the skewing of the T-cell receptor repertoire of tetramer-sorted, TRP-2-specific CD8(+) T lymphocytes, which showed a preferential alpha chain usage with a common CDR3 region.
De Palma
Raffaele
R
Department of Clinical and Experimental Medicine II, University of Naples, Naples, Italy.
Marigo
Ilaria
I
Del Galdo
Francesco
F
De Santo
Carmela
C
Serafini
Paolo
P
Cingarlini
Sara
S
Tüting
Thomas
T
Lenz
Julia
J
Basso
Giuseppe
G
Milan
Gabriella
G
Zanovello
Paola
P
Bronte
Vincenzo
V
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D007114:Immunization; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014614:Vaccines, Synthetic / Q000627:therapeutic use*
D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase