Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway

Abstract

T raditionally, heat shock proteins (HSP) 5 are regarded as chaperones assisting protein folding and translocation. However, HSP can also serve as cytokines that can stimulate dendritic cells (DC) and macrophages to produce proinflammatory cytokines and chemokines (1-5). More importantly, HSP derived from tumor cells are capable of chaperoning tumor Ags to DC and then cross-presenting the Ags to T cells (6). HSP70 proteins, including the constitutively expressed cognate HSP70 (HSC70 or HSP73), the stress-inducible HSP70 (HSP70i or HSP72), and the mitochondrial HSP70 (HSP75), constitute the most conserved class of all HSP. Previous reports have shown that HSP can be released from various cells via passive (e.g., HSP released during cell injury conditions, such as surgery, excessive exercise, and necrosis) and active (e.g., translocation of HSP to plasma membrane and subsequent secretion) pathways (3-5). However, the roles of HSP70 proteins released from tumor cells in the induction of antitumor immunity and the underlying mechanisms have not been fully elucidated.Hyperthermia (HT) has been reported to enhance the immunogenecity of cancer cells concomitantly with expression of HSP (7,8). Recent reports demonstrate that heat stress (HS) can induce the cell surface expression and the release of HSP70, HSP90, and gp96 (glucose-regulated protein 94; Grp94) (1-5). However, the underlying mechanisms that local HT can initiate antitumor immunity via released HSP and via subsequent activation of DC still lack direct evidence and thus need to be further investigated.During the investigations of local HT (42-43°C)-elicited antitumor immunity, we find that infiltration of DC and T cells within heat-stressed tumor is significantly increased. We thus hypothesize that chemokines, induced by HS, may be involved in the initiation of HT-elicited antitumor immunity by chemoattraction and activation of DC. Our studies show that HSP70 proteins simultaneously released by tumor cells can serve as autocrine and paracrine cytokines inducing the production of various chemokines by tumor cells and the activation of DC via TLR4 signaling pathway. Our data provide direct evidence for the important roles of releasable HSP in the initiation of antitumor immunity during local HT.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…57–59 Accordingly, protein DAMP-stimulated TLR4-signaling has been reported to be essential for anti-tumor immune priming in the context of radiation and chemotherapy. 60,61 Our results on TLR4 activation and its involvement in endothelial cell activation confirm these reports. However, if and to which extent this receptor-ligand axis may be accessible for targeted therapeutic intervention in combined modality approaches of radiotherapy needs to be clarified.…”

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

“…13,14 In this context, both HSP70 and HMGB1 appear to exert an immunostimulatory activity by promoting DC maturation through TLR4, which, in turn, leads to the induction of antigen-specific T cell-mediated antitumor immune responses. 15,16 In this regard, several studies highlight the importance of TLRs in the modulation of innate immune response in anticancer immunity. 17,18 More recently, low doses of chemotherapeutic drugs have been shown to induce immunogenic senescence and stimulate NK cell-mediated recognition and clearance of drugtreated tumor cells via the upregulation of NKG2D and DNAM-1 activating ligands on the surface of cancer cells.…”

Stress for maintaining memory: HSP70 as a mobile messenger for innate and adaptive immunity

“…Many studies show that the released extracellular HSP70 can function in a similar fashion to purified or recombinant HSP70 [2,11]. Recently, a potential mode of action of released HSP70 has been suggested.…”