title: HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice.
abstract: Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is approximately 4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB-neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-gamma and IL-4 production. Depletion studies revealed that CD8(+) T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4(+) T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4(+) CD25(+) regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-gamma-producing Th1 cells may be responsible for partial protection of CD4(+) T cells against the mammary tumor challenge, whereas CD4(+)CD25(+) regulatory T cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-gamma-producing T cells against spontaneous mammary tumors and that up-regulation of CD4(+) CD25(+) regulatory T cells may prevent complete eradication of the tumor following immunotherapy.
authors.affiliation: Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. masoud.manjili@roswellpark.org
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Martin
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.forename: Robert
authors.initials: R
authors.lastname: Henderson
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D015375:Receptors, Interleukin-2; D014614:Vaccines, Synthetic