Tumor-Derived Heat Shock Protein 70 Peptide Complexes Are Cross-Presented by Human Dendritic Cells

Noeßner, Elfriede; Gastpar, Robert; Milani, Valeria; Brandl, Anna; Hutzler, Peter; Kuppner, M. C.; Roos, Miriam; Kremmer, Elisabeth; Asea, Alexzander; Calderwood, Stuart K.; Issels, Rolf D.

doi:10.4049/jimmunol.169.10.5424

Cited by 241 publications

(171 citation statements)

References 55 publications

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“…It has been reported that intratumoral injection of DCs induced antitumor effects. 33,34 In addition, HSP70-enhanced antigen uptake 19 and HSP70-induced DC maturation 20,21 have been reported. This indicates that injection of DCs directly into tumors releasing HSP70 after hyperthermia using magnetite nanoparticles is a possible approach for immune induction.…”

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confidence: 98%

“…Furthermore, it has been revealed that HSPs play important roles in delivering antigens to antigen-presenting cells (APCs) and maturating dendritic cells (DCs) as danger signals. [19][20][21][22] DCs are the most potent APCs and can induce an immune response to tumors via antigen uptake and maturation. 23 The efficient isolation and preparation of both human and murine DCs is now possible.…”

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confidence: 99%

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Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

Tanaka

Ito

Kobayashi

et al. 2005

Intl Journal of Cancer

110

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Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in regulating immune responses in cancer and have recently been shown to be activated by heat shock proteins (HSPs). We previously reported that HSP70 expression after hyperthermia induces antitumor immunity. Our hyperthermia system using magnetite cationic liposomes (MCLs) induced necrotic cell death that was correlated with HSP70 release. In the present study, we investigated the therapeutic effects of DC therapy combined with MCL-induced hyperthermia on mouse melanoma. In an in vitro study, when immature DCs were pulsed with mouse B16 melanoma cells heated at 43°C, major histocompatibility complex (MHC) class I/II, costimulatory molecules CD80/ CD86 and CCR7 in the DCs were upregulated, thus resulting in DC maturation. C57BL/6 mice bearing a melanoma nodule were subjected to combination therapy using hyperthermia and DC immunotherapy in vivo by means of tumor-specific hyperthermia using MCLs and directly injected immature DCs. Mice were divided into 4 groups: group I (control), group II (hyperthermia), group III (DC therapy) and group IV (hyperthermia 1 DC therapy). Complete regression of tumors was observed in 60% of mice in group IV, while no tumor regression was seen among mice in the other groups. Increased cytotoxic T lymphocyte (CTL) and natural killer (NK) activity was observed on in vitro cytotoxicity assay using splenocytes in the cured mice treated with combination therapy, and the cured mice rejected a second challenge of B16 melanoma cells. This study has important implications for the application of MCL-induced hyperthermia plus DC therapy in patients with advanced malignancies as a novel cancer therapy. ' 2005 Wiley-Liss, Inc.Key words: hyperthermia; dendritic cell; antitumor immunity; magnetite cationic liposome; melanoma Hyperthermia has been used for many years to treat a wide variety of tumors in both experimental animals and patients. 1 The most commonly used heating method in clinical settings is capacitive heating using a radiofrequency (RF) electric field. 2 However, the problem with capacitive heating using an RF electric field is the difficulty in heating only the local tumor region at the intended temperature without damaging normal tissue, because electromagnetic energy is conducted from outside the body by penetrating normal tissue and is imperfectly transduced to heat; the heating characteristics are influenced by various factors, such as tumor size, position of electrodes, and adhesion of electrodes at uneven sites. Magnetic nanoparticles have thus been applied to hyperthermia in an attempt to overcome these disadvantages. 3,4 Magnetic nanoparticles act as a transducer to change electromagnetic energy to heat; such nanoparticles generate heat in an alternating magnetic field (AMF) due to hysteresis loss. As a result, only tissue accumulating magnetite nanoparticles is heated. 5 We subsequently developed magnetite cationic liposomes (MCLs) for use as an intracellular heating mediator. 6 MCLs were dev...

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confidence: 98%

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confidence: 99%

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

Tanaka

Ito

Kobayashi

et al. 2005

Intl Journal of Cancer

110

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“…This exogenous pathway is important for the development of CD8 ϩ CTL responses against tumors and infectious pathogens that do not have access to the classical MHC class I pathway. Administration of antigenic peptides in the context of purified HSPs induces potent CD8 ϩ T cell responses, indicating that HSP-peptide complexes can access the MHC class I endogenous Ag-presentation pathway (2,13,(15)(16)(17)(18)(19). Thus, shuttling exogenous peptides into the endogenous pathway might be a specialized function of HSPs.…”

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confidence: 99%

Efficient Cross-Presentation by Heat Shock Protein 90-Peptide Complex-Loaded Dendritic Cells via an Endosomal Pathway

Kurotaki

Tamura

et al. 2007

The Journal of Immunology

109

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It is well-established that heat shock proteins (HSPs)-peptides complexes elicit antitumor responses in prophylactic and therapeutic immunization protocols. HSPs such as gp96 and Hsp70 have been demonstrated to undergo receptor-mediated uptake by APCs with subsequent representation of the HSP-associated peptides to MHC class I molecules on APCs, facilitating efficient cross-presentation. On the contrary, despite its abundant expression among HSPs in the cytosol, the role of Hsp90 for the cross-presentation remains unknown. We show here that exogenous Hsp90-peptide complexes can gain access to the MHC class I presentation pathway and cause cross-presentation by bone marrow-derived dendritic cells. Interestingly, this presentation is TAP independent, and followed chloroquine, leupeptin-sensitive, as well as cathepsin S-dependent endosomal pathways. In addition, we show that Hsp90-chaperoned precursor peptides are processed and transferred onto MHC class I molecules in the endosomal compartment. Furthermore, we demonstrate that immunization with Hsp90-peptide complexes induce Ag-specific CD8+ T cell responses and strong antitumor immunity in vivo. These findings have significant implications for the design of T cell-based cancer immunotherapy.

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“…In addition, we have shown that human Hsp70 from melanoma cells can chaperone tumor-associated peptides (tyrosinase) and deliver them to DCs allowing cross-presentation and T cell stimulation (16). Recently, we used recombinant human (rhu)Hsp70 to define in more detail the critical parameters for the induction of immune effector responses (17).…”

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confidence: 99%

Calcium Signaling in Dendritic Cells by Human or Mycobacterial Hsp70 Is Caused by Contamination and Is Not Required for Hsp70-mediated Enhancement of Cross-presentation

Bendz

Marincek

Momburg

et al. 2008

Journal of Biological Chemistry

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Extracellular heat shock proteins (HSPs) can stimulate antigen-specific immune responses. Using recombinant human (rhu)Hsp70, we previously demonstrated that through complex formation with exogenous antigenic peptides, rhuHsp70 can enhance cross-presentation by antigen-presenting cells (APCs) resulting in stronger T cell stimulation. T cell stimulatory activity has also been described for mycobacterial (myc)Hsp70. MycHsp70-assisted T cell activation has been reported to act through the binding of mycHsp70 to chemokine receptor 5 (CCR5), calcium signaling, phenotypic maturation, and cytokine secretion by dendritic cells (DCs). We report that highly purified rhuHsp70 and mycHsp70 proteins both strongly enhance cross-presentation of exogenous antigens. Augmentation of cross-presentation was seen for different APCs, irrespective of CCR5 expression. Moreover, neither of the purified Hsp70 proteins induced calcium signals in APCs. Instead, calcium signaling activity was found to be caused by contaminating nucleotides present in Hsp70 protein preparations. These results refute the hypothesis that mycHsp70 proteins require CCR5 expression and calcium signaling by APCs for enhanced antigen cross-presentation for T cell stimulation.Recent evidence has demonstrated that heat shock proteins (HSPs), 2 in addition to their roles as chaperones, can stimulate antigen-specific immune responses (1). This immune stimulatory activity is thought to be activated after HSPs are released from cells either through necrosis or induced secretion (2-5).In their role as molecular chaperones, most HSPs exist in complexes with hydrophobic polypeptides. The contact of extracellular HSP:peptide complexes with dendritic cells (DCs) is thought to result in the efficient transfer of the chaperoned peptides into the antigen-presentation pathway of DCs allowing antigen-specific T cell activation.Mechanistically, HSP binding to surface receptors and HSP-induced signaling events are thought to be involved in antigen transfer to DCs and subsequent T cell stimulation. In this regard, a number of potential HSP receptors have been reported (6 -9). Among these, CD40 and chemokine receptor 5 (CCR5) represent two interesting possibilities as these molecules are intricately linked to T cell and DC biology (10, 11). In this regard, CCR5 has been reported to act as a pattern recognition receptor for mycobacterial (myc)Hsp70 thus facilitating mycobacterial defense through mycHsp70-induced DC activation and subsequent T cell stimulation. The binding of mycHsp70 to CCR5, calcium signaling in myeloid DCs, phenotypic maturation, and cytokine secretion of DCs have been reported to underlie mycHsp70-assisted T cell activation (12, 13).We have previously demonstrated that CCR5 can mediate unique signaling events (14, 15). In addition, we have shown that human Hsp70 from melanoma cells can chaperone tumor-associated peptides (tyrosinase) and deliver them to DCs allowing cross-presentation and T cell stimulation (16). Recently, we used recombinant human (rhu)Hsp70 to def...

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Tumor-Derived Heat Shock Protein 70 Peptide Complexes Are Cross-Presented by Human Dendritic Cells

Cited by 241 publications

References 55 publications

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

Efficient Cross-Presentation by Heat Shock Protein 90-Peptide Complex-Loaded Dendritic Cells via an Endosomal Pathway

Calcium Signaling in Dendritic Cells by Human or Mycobacterial Hsp70 Is Caused by Contamination and Is Not Required for Hsp70-mediated Enhancement of Cross-presentation

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