Enhancement of human melanoma antigen expression by IFN-beta.
Although many immunotherapeutic investigations have focused on improving the effector limb of the antitumor response, few studies have addressed preventing the loss of tumor-associated Ag (TAA) expression, associated with immune escape by tumors. We found that TAA loss from human melanomas usually results from reversible gene down-regulation, rather than gene deletion or mutation. Previously, we showed that inhibitors of MAPK-signaling pathways up-regulate TAA expression in melanoma cell lines. We have now identified IFN-beta as an additional stimulus to TAA expression, including Melan-A/MART-1, gp100, and MAGE-A1. IFN-beta (but neither IFN-alpha nor IFN-gamma) augmented both protein and mRNA expression of melanocytic TAA in 15 melanoma lines (irrespective of initial Ag-expression levels). Treatment of low Ag melanoma lines with IFN-beta increased expression of melanocyte-lineage Ags, inducing susceptibility to lysis by specific CTLs. Treatment with IFN-beta also enhances expression of class I HLA molecules, thereby inducing both nominal TAA and the presenting HLA molecule. Data from fluorescent cellular reporter systems demonstrated that IFN-beta triggers promoter activation, resulting in augmentation of Ag expression. In addition to enhancing TAA expression in melanomas, IFN-beta also stimulated expression of the melanocytic Ag gp100 in cells of other neural crest-derived tumor lines (gliomas) and certain unrelated tumors. Because IFN-beta is already approved for human clinical use in other contexts, it may prove useful as a cotreatment for augmenting tumor Ag expression during immunotherapy.
Dunn
Ian S
IS
CytoCure, Beverly, MA 01915, USA.
Haggerty
Timothy J
TJ
Kono
Michihiro
M
Durda
Paul J
PJ
Butera
David
D
Macdonald
David B
DB
Benson
Elizabeth M
EM
Rose
Lenora B
LB
Kurnick
James T
JT
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016899:Interferon-beta