title: Heat shock protein-90 inhibitors enhance antigen expression on melanomas and increase T cell recognition of tumor cells.
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.
authors.affiliation: CytoCure LLC, Suite 430C, 100 Cummings Center, Beverly, MA, United States of America; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Haggerty
authors.affiliation: CytoCure LLC, Suite 430C, 100 Cummings Center, Beverly, MA, United States of America.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Dunn
authors.affiliation: CytoCure LLC, Suite 430C, 100 Cummings Center, Beverly, MA, United States of America.
authors.forename: Lenora B
authors.initials: LB
authors.lastname: Rose
authors.affiliation: CytoCure LLC, Suite 430C, 100 Cummings Center, Beverly, MA, United States of America.
authors.forename: Estelle E
authors.initials: EE
authors.lastname: Newton
authors.affiliation: Department of Internal Medicine, Catholic University, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Pandolfi
authors.affiliation: CytoCure LLC, Suite 430C, 100 Cummings Center, Beverly, MA, United States of America; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: James T
authors.initials: JT
authors.lastname: Kurnick
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007167:Immunotherapy; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D058950:Melanoma-Specific Antigens / Q000235:genetics*; D051379:Mice; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D058950:Melanoma-Specific Antigens; D048493:Proto-Oncogene Proteins B-raf