Adoptive transfer of an anti-MART-1(27-35)-specific CD8+ T cell clone leads to immunoselection of human melanoma antigen-loss variants in SCID mice.
The identification of appropriate mouse models could be useful in carefully evaluating the actual role of the in vivo development of antigen-loss variants during antigen-specific vaccine therapy of human tumors. In this study we investigated the level of efficacy of a MART-1/Melan-A-specific CD8+ T cell clone against its autologous melanoma in a severe combined immunodeficiency (SCID) mouse model, in which the tumor cells expressed in vivo heterogeneous and suboptimal levels of MART-1. The subcutaneous co-injection of the MART-1/Melan-A-reactive T cell clone A42 with MART-1/Melan-A+ autologous human melanoma cells into SCID mice caused a total inhibition of tumor growth. However, the systemic treatment with A42 clone lymphocytes resulted in only 50-60% inhibition of tumor growth, although the T cell clone targeted the tumors and the MART-1+ cells virtually disappeared from the tumors. This study suggests that an immunotherapy based on the expansion of an antigen-specific T cell clone generated in vitro is highly efficient in abolishing tumor growth when the target antigen is fully expressed, but leads to in vivo immunoselection of antigen-loss variants in the presence of suboptimal levels of antigen expression. Furthermore, this work shows that human tumors/SCID mouse models may be useful in evaluating the in vivo efficacy of adoptive immunotherapies.
Lozupone
Francesco
F
Laboratory of Immunology, Istituto Superiore di Sanità, Rome, Italy.
Rivoltini
Licia
L
Luciani
Francesca
F
Venditti
Massimo
M
Lugini
Luana
L
Cova
Agata
A
Squarcina
Paolo
P
Parmiani
Giorgio
G
Belardelli
Filippo
F
Fais
Stefano
S
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002999:Clone Cells / Q000276:immunology / Q000637:transplantation; D000939:Epitopes / Q000032:analysis / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000032:analysis / Q000276:immunology*; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation; D019139:Tumor Escape; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D000939:Epitopes; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins