The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells

Abstract

Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 (HSP70), and HSP70-positive T-EVs are known to trigger anti-tumor immune responses. Moreover, extracellular HSP70 acts as an immunogen that contributes to the cross-presentation of major histocompatibility complex (MHC) class I molecules. However, the release of DAMPs, including HSP70, may also induce chronic inflammation or suppress immune cell activity, promoting tumor growth. Here, we summarize the current knowledge on soluble, membrane-bound, and EV-associated HSP70 regarding their functions in regulating tumor-associated immune cells in the tumor microenvironment. The molecular mechanisms involved in the translocation of HSP70 to the plasma membrane of tumor cells and its release via exosomes or soluble proteins are summarized. Furthermore, perspectives for immunotherapies aimed to target HSP70 and its receptors for cancer treatment are discussed and presented.

Keywords: HSP70; cancer; extracellular vesicles; immune modulation; tumor microenvironment.

Figure 1

Translocation of extracellular HSP70 (exHSP70). Cellular stress leads to the translocation of HSP70 via different potential mechanisms. In particular, membrane-associated HSP70 (mHSP70, green) can be found in lipid rafts, mainly interacting with globotriaosylceramide 3 (Gb3). Moreover, HSP70 can interact with phosphatidylserine (PS), leading to its integration into the plasma membrane. Oligomerized HSP70 was also reported to integrate into the plasma membrane directly. HSP70 can also be released into or onto extracellular vesicles (evHSP70, red), by either budding of the plasma membrane (ectosomes) or by an endolysosomal pathway (exosomes). Soluble HSP70 (sHSP70, blue) can be secreted either passively during cell necrosis or actively via secretory granules or lysosomes. ESE: early sorting endosomes; LSE: late sorting endosomes; MVB: multivesicular bodies; EV: extracellular vesicles; PS: phosphatidylserine; Gb3: globotriaosylceramide 3; HSP70: heat shock protein 70.

Figure 2

Pro-tumorigenic functions of exHSP70. MDSC: myeloid-derived suppressor cell; RAGE: receptor for advanced glycosylation endproducts; GSK-3β: glycogen synthase kinase-3β; NO: nitride oxide; TLR: Toll-like receptor; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; HSF1: heat shock factor 1; VEGF: vasculogenic endothelial growth factor; pSTAT3: phosphorylated signal transducer and activator of transcription 3; ROS: reactive oxygen species; MyD88: myeloid differentiation primary response 88; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; MMP: matrix metalloproteinases; HSP70: heat shock protein 70.

Figure 3

Anti-tumorigenic functions of exHSP70. FASL: Fas ligand; TNFR1: tumor necrosis factor receptor 1; APC: antigen-presenting cell; NK: natural killer; DC: dendritic cell; MHC: major histocompatibility complex; MICA: MHC class I polypeptide–related sequence A; TREM-1: triggering receptor expressed on myeloid cells 1; INF-γ: interferon-gamma; TNF-α: tumor necrosis factor-alpha; IL-2: interleukin-2; Tag7: peptidoglycan recognition protein; CXCL10: C-X-C motif chemokine ligand 10; CCL5: Chemokine (C-C motif) ligand 5; HSP70: heat shock protein 70.