Enhanced Immunogenicity of Heat Shock Protein 70 Peptide Complexes from Dendritic Cell-Tumor Fusion Cells

Abstract

We have developed a molecular chaperone-based tumor vaccine that reverses the immune tolerance of cancer cells. Heat shock protein (HSP) 70 extracted from fusions of dendritic (DC) and tumor cells (HSP70.PC-F) possess superior properties such as stimulation of DC maturation and T cell proliferation over its counterpart from tumor cells. More importantly, immunization of mice with HSP70.PC-F resulted in a T cell-mediated immune response including significant increase of CD8 T cells and induction of the effector and memory T cells that was able to break T cell unresponsiveness to a nonmutated tumor Ag and provide protection of mice against challenge with tumor cells. By contrast, the immune response to vaccination with HSP70-PC derived from tumor cells is muted against such nonmutated tumor Ag. HSP70.PC-F complexes differed from those derived from tumor cells in a number of key manners, most notably, enhanced association with immunologic peptides. In addition, the molecular chaperone HSP90 was found to be associated with HSP70.PC-F as indicated by coimmunoprecipitation, suggesting ability to carry an increased repertoire of antigenic peptides by the two chaperones. Significantly, activation of DC by HSP70.PC-F was dependent on the presence of an intact MyD88 gene, suggesting a role for TLR signaling in DC activation and T cell stimulation. These experiments indicate that HSP70-peptide complexes (PC) derived from DC-tumor fusion cells have increased their immunogenicity and therefore constitute an improved formulation of chaperone protein-based tumor vaccine.

A heat shock protein gene (Hsp70.1) is critically involved in the generation of the immune response to myelin antigen

“…It has been shown for both MHC class I-and II-dependent systems that hsp70 complexes with proteins are more immunogenic than proteins alone [20][21][22][23][24][25][26][27][28][29]. This has been related to enhancement of antigen presentation by hsp.…”

“…While most data on the contribution of hsp-peptide interactions have addressed immune responses involving MHC class Idependent pathways [21][22][23][24], more recent results from this [25], and other [26][27][28][29] laboratories indicate that hsp are also capable of participating in antigen presentation in MHC class II-dependent pathways. In this respect, hsp70 is a major hsp implicated in the formation of immunogenic complexes and the facilitation of MHC presentation.…”

Co-Inhibition of HSP70/HSP90 Synergistically Sensitizes Nasopharyngeal Carcinoma Cells to Thermotherapy

“…Especially of interest is whether HSP70 or HSP90 can help present antigens to antigen-presenting cells in different ways and thus induce antitumor immunity. [35][36][37][38] In the current study, the possible immune effects of co-inhibition of HSP70 and HSP90 were excluded because of the immune defaults of nude mice. Nevertheless, the antitumor effects of co-inhibition of HSP70 and HSP90 and subsequent sensitizing activity to thermotherapy are attractive for further application.…”

Evidence of a role for both anti-Hsp70 antibody and endothelial surface membrane Hsp70 in atherosclerosis

“…An important question that remains unanswered is how does BD091 promote atherosclerosis? Although Hsp70 is considered intracellular, cell membrane expression is observed in response to various types of stresses on tumor cells (SinghJasuja et al 2001;Srivastava 2002;Campisi et al 2003;Enomoto et al 2006). In the present study, we aimed to identify the evidence of a role for both anti-Hsp70 antibody and endothelial surface membrane Hsp70 in atherosclerosis.…”