IFN-gamma gene transfer restores HLA-class I expression and MAGE-3 antigen presentation to CTL in HLA-deficient small cell lung cancer.
In this study, we have analyzed the possibility of inducing T cell responses against small cell lung cancer (SCLC), a still incurable tumor, by cytokine gene transfer approaches. By RT-PCR analysis most SCLC expressed the CTL-defined tumor antigens MAGE-3 (10/11), MAGE-1 (7/11) and less frequently BAGE (4/11) and GAGE1,2 (4/11). Although the surface expression of HLA class I molecules was low on most SCLC, thus preventing CTL recognition, treatment of the cells with IFN-gamma enhanced HLA-class I levels in all cases. Two MAGE3+ SCLC cell lines displaying the A2 HLA-class I allele, involved in MAGE-3 antigen presentation to CTL, were stably transfected with the IFN-gamma gene (alone or co-transfected with IL-2). IFN-gamma-transfected cells displayed a clearcut increase in expression of HLA-class I and beta 2-microglobulin at both protein and mRNA level, and of TAP-1 and TAP-2 mRNA. Perhaps more importantly, IFN-gamma transfected cells were recognized by the MAGE-3-specific A2-restricted antimelanoma CTL clone 297/22, while unmodified cells or cells transfected with the IL-2 gene alone were not. These data indicate that IFN-gamma gene transfection into HLA-deficient SCLC cells is able to restore their ability to present endogenous tumor antigens to CTL and that IFN-gamma gene transfer approaches may be attempted to induce specific CTL responses in SCLC.
Traversari
C
C
DIBIT HS Raffaele, Milano, Italy.
Meazza
R
R
Coppolecchia
M
M
Basso
S
S
Verrecchia
A
A
van der Bruggen
P
P
Ardizzoni
A
A
Gaggero
A
A
Ferrini
S
S
D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D015152:Blotting, Northern; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D007371:Interferon-gamma