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.

Elevated circulating Hsp70 levels are correlative for malignancies in different mammalian species

“…Extracellular Hsp70 is enhancing tumor growth and migration by promoting multiple pro-oncogenic pathways including the PI3K/Akt and phosphorylated STAT3 pathways (Lee et al 2006 ; Diao et al 2015 ; Park et al 2017 ). Moreover, extracellular Hsp70 levels have been found to affect tumor associated immune responses (Linder and Pogge von Strandmann 2021 ; Pockley and Henderson 2018 ) and exosomal Hsp70 acts as a regulator of tumor-associated immune cells which determines immunosurveillance and evasion (Multhoff et al 2001 ; Lee et al 2006 ; Specht et al 2015 ; Barreca et al 2017 ; Taha et al 2019 ).…”

In Situ Antigen‐Capturing Nanochaperone Toward Personalized Nanovaccine for Cancer Immunotherapy

“…[ 16 ] For example, heat shock proteins (HSPs) can chaperone TAAs, protect them and facilitate their uptake by APCs with subsequently endorsed cross‐presentation. [ 17 ] Inspired by natural chaperones, various chaperone mimetic materials have been designed and used to regulate protein (re)folding, protect protein, and mediate protein transport. [ 18 ] Recently, in a proof‐of‐concept study, we first time demonstrated that the mixed‐shell polymeric micelle (MSPM)‐based nanochaperone (nChap) was a promising nanomaterial for fabrication of nanovaccine to enhance cancer immunotherapy.…”

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

“…For many years, exosomes have been thought to only function as molecular carriers that carry waste from cells; however, it has become clear that EVs affect various biological processes and diseases, including immune responses and cancer [ 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 ]. Nonetheless, it is difficult to identify these exosomes.…”