Abstract
In an effort to enhance antigen-specific T cell recognition of cancer cells, we have examined numerous modulators of antigen-expression. In this report we demonstrate that twelve different Hsp90 inhibitors (iHsp90) share the ability to increase the expression of differentiation antigens and MHC Class I antigens. These iHsp90 are active in several molecular and cellular assays on a series of tumor cell lines, including eleven human melanomas, a murine B16 melanoma, and two human glioma-derived cell lines. Intra-cytoplasmic antibody staining showed that all of the tested iHsp90 increased expression of the melanocyte differentiation antigens Melan-A/MART-1, gp100, and TRP-2, as well as MHC Class I. The gliomas showed enhanced gp100 and MHC staining. Quantitative analysis of mRNA levels showed a parallel increase in message transcription, and a reporter assay shows induction of promoter activity for Melan-A/MART-1 gene. In addition, iHsp90 increased recognition of tumor cells by T cells specific for Melan-A/MART-1. In contrast to direct Hsp90 client proteins, the increased levels of full-length differentiation antigens that result from iHsp90 treatment are most likely the result of transcriptional activation of their encoding genes. In combination, these results suggest that iHsp90 improve recognition of tumor cells by T cells specific for a melanoma-associated antigen as a result of increasing the expressed intracellular antigen pool available for processing and presentation by MHC Class I, along with increased levels of MHC Class I itself. As these Hsp90 inhibitors do not interfere with T cell function, they could have potential for use in immunotherapy of cancer.
Highlights
While there is widespread interest in mobilizing anti-tumor immunity, there remain barriers to immunotherapy [1] [2]
CCT018159 was highly effective at induction of MHC Class I antigen on the murine melanoma (6.8 fold induction), and PU-H71 induced strong increases in TRP-2 in these same B16 murine melanoma cells, indicating differential sensitivity of different cell lines to the various iHsp90s
Using the Melan-A/MART-1 promoter EGFP system in the melanoma cell line MU89, we showed that cells treated with 4 separate Hsp90 inhibitors (17-AAG, 17-AEP, CCT018159, and PU-H71) significantly enhanced the fluorescent reporter signal as early as 2 days (Fig. 4)
Summary
While there is widespread interest in mobilizing anti-tumor immunity, there remain barriers to immunotherapy [1] [2]. Through its role in regulating the conformation, stability and function of several key oncogenic client proteins, Hsp is essential in maintaining malignant transformation and in increasing the survival, growth, and invasive potential of cancer cells, including melanomas [18] [19]. Several members of this drug class have been tested in human clinical trials [20], and while the drugs may slow tumor growth, to date none have succeeded as single agents [21]. The iHsp90s are able to enhance antigen expression on the tumor cells while retaining T-cell function [16], suggesting that this class of drugs could be utilized in immunotherapy to enhance tumor targeting
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