Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line.
Recent evidence suggests that deficient HLA Class I expression in SCLC lines may be due, in part, to down-regulation of TAP-1 and TAP-2 expression, and, thus, deficient antigen processing. Given the capability of the multidrug transporter mediating MDR, P-gp, to transport peptides, we hypothesized that P-gp may substitute for TAP-1/TAP-2 and enhance antigen processing in SCLC. To investigate this, we studied the H69 line (parent SCLC) and VPR-2 (MDR subline selected in etoposide, P-gp +). HLA-A,B,C expression was significantly increased in VPR-2 cells relative to H69, and was much more inducible with IFN-gamma. TAP-1 and TAP-2 were expressed at low levels in both lines. Differential induction of TAP-1 expression with IFN-gamma exposure was observed, with a dramatic increase in VPR-2 cells, and no change in H69. TAP-2 expression was enhanced in both lines with IFN-gamma, but to a greater degree in VPR-2. VPR-2 cells were resistant to LAK killing relative to H69, and were minimally sensitized with IFN-gamma. In contrast, IFN-gamma enhanced susceptibility of H69 to LAK killing 3-fold. The direct correlation between enhancement of HLA-A,B,C expression by IFN-gamma and the differential inducibility of TAP-1 and TAP-2 expression in P-gp-SCLC lines is novel. Relative LAK sensitivity of H69 and its increase by IFN-gamma may have clinical implications.
Fisk
B
B
Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
Ioannides
C G
CG
Aggarwal
S
S
Wharton
J T
JT
O'Brian
C A
CA
Restifo
N
N
Glisson
B S
BS
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000235:genetics; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000276:immunology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D017931:DNA Primers; D006680:HLA Antigens; D011994:Recombinant Proteins; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D005047:Etoposide; D007371:Interferon-gamma