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1
* CytoCure, Beverly, MA 01915;
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114; and
Department of Immunopathology, Westmead Hospital, Sydney, New South Wales, Australia
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-
as an additional stimulus to TAA expression, including Melan-A/MART-1, gp100, and MAGE-A1. IFN- (but neither IFN-
nor IFN-
) 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- increased expression of melanocyte-lineage Ags, inducing susceptibility to lysis by specific CTLs. Treatment with IFN- 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- triggers promoter activation, resulting in augmentation of Ag expression. In addition to enhancing TAA expression in melanomas, IFN- also stimulated expression of the melanocytic Ag gp100 in cells of other neural crest-derived tumor lines (gliomas) and certain unrelated tumors. Because IFN- is already approved for human clinical use in other contexts, it may prove useful as a cotreatment for augmenting tumor Ag expression during immunotherapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the National Institutes of Health: R43-CA86153, R43-CA96271, and R43-CA94700 and from the International Cancer Research Scholarship.
2 Address correspondence and reprint requests to Dr. James T. Kurnick, CytoCure, 100 Cummings Center, Suite 430C, Beverly, MA 01915. E-mail address: kurnick{at}massmed.org
3 Abbreviations used in this paper: CDK2, cyclin-dependent kinase 2; DGKA, diacylglycerol kinase; Q-PCR, quantitative PCR; CTA, cancer testis Ag; TAA, tumor-associated Ag; TIL, tumor-infiltrating lymphocyte.
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