Optimal T cell activation by melanoma cells depends on a minimal level of antigen transcription.
We reported previously that a large fraction of melanoma cell lines induced a suboptimal activation of specific CTL clones, characterized by good tumor cell lysis but no detectable IL-2 production. Using synthetic peptides, we demonstrated recently that this was due to expression of subthreshold levels of appropriate MHC-peptide complexes. We measure here by semiquantitative reverse transcription-PCR the expression of two melanoma Ag (NA17-A and Melan-A/MART-1) mRNAs in 13 melanoma cell lines and analyze the responses to these cell lines of specific HLA-A2-restricted CTL clones. In line with the idea that the density of MHC-antigenic peptide complexes on melanoma cells is a direct function of the Ag's mRNA level, we found that CTL lysis was grossly proportional to this level. We also established that a minimal level of transcription is required for melanoma cells to induce IL-2 secretion. Interestingly, all cell lines that expressed the Ag above this minimal level, either spontaneously or after gene transfection, stimulated the secretion by tumor-infiltrating lymphocyte of IL-2 amounts proportional to Ag expression unless they exhibited a defective expression of intracellular adhesion molecule-1 or LFA-3 molecules or a low expression of the restricting HLA element. These results indicate that optimal activation and therefore, doubtless, full functionality of melanoma-specific CTL clones critically depend on the mRNA level of the Ag in tumor cells and also on a minimal expression of the HLA restriction element, intracellular adhesion molecule-1, and LFA-3. These data provide a rationale for a better selection of patients to be included in Ag-specific immunization protocols.
Labarriere
N
N
INSERM Unit 211 and Faculty of Sciences of Nantes, France.
Diez
E
E
Pandolfino
M C
MC
Viret
C
C
Guilloux
Y
Y
Le Guiner
S
S
Fonteneau
J F
JF
Dreno
B
B
Jotereau
F
F
D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000378:metabolism; D018968:CD58 Antigens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D018968:CD58 Antigens; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018799:Intercellular Adhesion Molecule-1