Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity

Hanping Feng,Yi Zeng,Michael W Graner,Anna Likhacheva,Emmanuel Katsanis

doi:10.1182/blood-2002-05-1580

Abstract

AbstractWe have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis. Stressed apoptotic cells express heat shock proteins on their plasma membranes and dendritic cells are capable of distinguishing them from nonstressed apoptotic cells. Here we provide evidence that when purified heat shock protein 70 or chaperone-rich cell lysate (CRCL) from syngeneic normal tissue is used as an adjuvant with nonimmunogenic apoptotic tumor cells in vaccination, potent antitumor immunity can be generated. This antitumor immunity is mediated by T cells because antitumor effects are not observed in either severe combined immunodeficiency or T cell–depleted mice. We further demonstrate that vaccination of mice with apoptotic tumor cells mixed with liver-derived CRCL as adjuvant were capable of enhancing the production of TH1 cytokines, inducing specific cytotoxic T lymphocytes and eliciting long-lasting antitumor immunity. Stress proteins from autologous normal tissue components therefore can serve as danger signals to enhance the immunogenicity of apoptotic tumor cells and stimulate tumor-specific immunity

Highlights

We have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis
We have demonstrated that stressed apoptotic tumor cells express heat shock proteins (HSPs) on their surface, which appear to play a critical role in enhancing their immunogenicity.[7,8]
We found that coinjection of HSP70 significantly delayed tumor growth compared with mice that were injected with AP20187treated cells alone (Figure 1A)

Summary

Introduction

We have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis. Several mechanisms have been proposed to explain how these HSP complexes, which carry tumor-derived peptides as part of their chaperoning functions, can elicit immune responses.[15,16,17] One possible hypothesis is that chaperone complexes supply both antigens and danger signals to the immune system.[15,16,17] These adjuvant effects/danger signals activate APCs, such as DCs, leading to more efficient processing and presentation of HSPchaperoned peptides.[18,19] We have previously reported that heat stress induces HSP expression on the surface of apoptotic 12B1-D1 cells and increases their immunogenicity.[7,8] We reasoned that the immunogenicity of nonstressed apoptotic cells (which do not express HSPs on their surface) may be enhanced if an exogenous source of HSPs is present at the vaccination site. FS-IEF is a simple and rapid method for the generation of natural vaccine adjuvants active in enhancing immunogenicity of apoptotic tumor cells resulting in the generation of potent antitumor immunity

Methods

Results

Conclusion