HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice.
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.
Manjili
Masoud H
MH
Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. masoud.manjili@roswellpark.org
Wang
Xiang-Yang
XY
Chen
Xing
X
Martin
Thomas
T
Repasky
Elizabeth A
EA
Henderson
Robert
R
Subjeck
John R
JR
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
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