Heat Shock Protein-90 Inhibitors Enhance Antigen Expression on Melanomas and Increase T Cell Recognition of Tumor Cells

• Published in: PloS one Vol. 9; no. 12; p. e114506
• Main Authors: Haggerty, Timothy J., Dunn, Ian S., Rose, Lenora B., Newton, Estelle E., Pandolfi, Franco, Kurnick, James T.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.12.2014; Public Library of Science (PLoS)
• Subjects: Animals; Antigen presentation; Antigens; Biology and Life Sciences; Biotechnology; Cancer; Cancer therapies; Cell Proliferation - drug effects; Cell recognition; Differentiation; Gene Expression Regulation, Neoplastic - drug effects; Genetic research; Glioma cells; Gliomas; Glycoprotein gp100; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; Immunomodulation; Immunotherapy; Inhibitors; Kinases; Kinetics; Lymphocytes; Lymphocytes T; Major histocompatibility complex; MAP Kinase Signaling System - drug effects; MART-1 antigen; MART-1 gene; Medicine and Health Sciences; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Melanoma-associated antigen; Melanoma-Specific Antigens - genetics; Mice; Modulators; Molecular chains; Mutation; Proteins; Proto-Oncogene Proteins B-raf - genetics; Quantitative analysis; Recognition; Staining; T cells; T-Lymphocytes - immunology; Transcription activation; Tumor cell lines; Tumor cells; Tumors; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114506

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.