Abstract
Simple SummaryThe intracellular heat shock protein 70 (HSP70) is essential for cells to respond to stress, for instance, by refolding damaged proteins or inhibiting apoptosis. However, in cancer, HSP70 is overexpressed and can translocate to the extracellular milieu, where it emerged as an important modulator of tumor-associated immune cells. By targeting the tumor microenvironment (TME) through different mechanisms, extracellular HSP70 can trigger pro- or anti-tumorigenic responses. Therefore, understanding the pathways and their consequences is crucial for therapeutically targeting cancer and its surrounding microenvironment. In this review, we summarize current knowledge on the translocation of extracellular HSP70. We further elucidate its functions within the TME and provide an overview of potential therapeutic options.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.
Highlights
Introduction published maps and institutional affilHeat shock protein 70 (HSP70/HSPA1A/HSP72) is a molecular chaperone and belongs to the heat shock protein 70 (HSP70) family
This study further revealed that Membrane HSP70 (mHSP70) preferentially localizes in lipid rafts, which are microdomains enriched in cholesterol, glycosphingolipids, and protein receptors
One specific response is the upregulation of the inducible HSP70, subsequently protecting cells via chaperone activities or inhibiting apoptosis
Summary
HSP70 has several functions, including folding newly synthesized proteins, regulating protein activity, or preventing aggregation, indicating a cytosolic localization of the chaperone [1]. Mambula and Calderwood postulated an endolysosomal route as a mechanism for solubleHSP70 (sHSP70), as the secretion correlated with the lysosomal marker lysosomal-associated membrane protein 1 (LAMP1) and could be inhibited by lysosomotropic compounds [39] They showed that HSP70 could enter lysosomes via ATP-binding cassette (ABC) family transporter proteins [39]. The secreted chaperone was found to bind back to the plasma membrane, indicating an alternative route to the lipid raft-mediated pathway for membrane-associated HSP70 [39] Another way of HSP70 release was demonstrated by Evdonin et al, showing the formation of secretory-like granules upon inhibition of phospholipase C [32]. EV:protein extracellular vesicles; PS: phosphatidylserine; Gb3: globotriaosylceramide 3; HSP70: heat shock protein 70
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