Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion

Abstract

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

“…HSP90α is an inducible type of HSP in stressed conditions and cancer, while HSP90β is a constitutively expressed type of HSP [14,27]. We next examined whether both CDC37 and HSP90α could be involved in EMT properties in PC-3 cells.…”

“…Notably, HSPs and vesicles were co-released upon cell stress and cell damage such as molecular targeted therapeutic stress [21,22], anticancer therapeutic DNA damage stress [23,24], and HSS [25,26]. Extracellular HSPs are also known as alarmin or damage-/danger-associated molecular patterns (DAMP) that are released from cells upon tissue damage [27,28].…”

“…Notably, HSPs and vesicles were co-released upon cell stress and cell damage such as molecular targeted therapeutic stress [21,22], anticancer therapeutic DNA damage stress [23,24], and HSS [25,26]. Extracellular HSPs are also known as alarmin or damage-/danger-associated molecular patterns (DAMP) that are released from cells upon tissue damage [27,28].Extracellular vesicle (EV) is the generic term for particles naturally released from the cell that are delimited by lipid bilayer and cannot replicate, i.e., do not contain a functional nucleus [29]. EVs often contain a variety of molecular cargos such as proteins, small and large RNAs, DNA, lipid, glycans, mineral such as calcium, and metabolites that are secreted by cells [30][31][32][33].…”

“…In addition, the enhancement of EMT properties was often coupled with increased release of EVs [22,49]. These facts prompted us to make a concept of EMT-coupled vesicle release.Among many molecular cargos, HSPs are major signatures often found within sEV such as exosomes, ectosomes, and oncosomes [4,19,20,27]. According to the minimal information for studies of extracellular vesicles 2018 (MISEV2018), EV markers are categorized into five categories and the category 2 (cytosolic proteins recovered in EVs) includes heat shock cognate 70 (HSC70/HSPA8: essential for autophagy), HSP70, and HSP90β (HSP90AB1/HSP84), while category 4 (transmembrane, lipid-bound, and soluble proteins associated to other intracellular compartments than plasma membrane/endosomes) includes ER chaperones such as Grp94/HSP90B and BiP/HSPA5 [29].…”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…Altogether these results confirm the interest of targeting HSP110, at least in colorectal cancers, and probably in other types of cancer, such as B-cell lymphoma. Although HSPs are generally considered intracellular proteins, we now know that HSP110 can also be released to act extracellularly like HSP27, 70, and 90 [157][158][159]. The release of HSP110 from human intestinal epithelial cells has also been described, suggesting a role in the physiological process of epithelial renewal [160].…”