Heat Shock Proteins-Based Therapies for Cancer: History
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Heat shock proteins (HSPs) are extensively distributed throughout cells. They play a crucial role as molecular chaperones and regulate various cellular processes, such as metabolism, growth, differentiation, cell signaling, and programmed cell death. However, in cancers, HSPs are frequently overexpressed and associated with tumor advancement and metastasis, as well as in acquiring drug resistance against chemotherapeutic agents, leading to poor prognosis. Thus, the expression of HSPs can be modulated to imitate the cellular response against cancer cells by targeting the tumor microenvironment through different mechanisms.

  • heat shock proteins
  • molecular chaperones
  • cancer
  • HSP inhibitors

1. Introduction

Heat shock proteins (HSPs) are ubiquitous polypeptide proteins found mostly in every cell from prokaryotes to eukaryotes [1]. HSPs are essential cellular components contributing to the maintenance of cellular protein homeostasis and internal conditions under both moderate and damaged growth conditions [2,3]. It is commonly known that HSPs are involved in a variety of cellular functions, including protein synthesis, folding and assembly, translocation, conformational maintenance, and degradation during cellular processes. These proteins also contribute to the normal growth and development of cells [4,5]. They play essential roles in a myriad of cellular activities: assist in protein synthesis, prevent aggregation of unfolded or misfolded proteins that aid in proper folding and assembly to form functional structures, aid in the translocation of proteins for their proper localization within the cell, maintain proper conformation, thus preventing proteins to acquire potentially harmful structures, help in the degradation of misfolded proteins through proteolytic pathways such as the ubiquitin-proteasome system, and finally assist in the regular processes of cellular growth and development by playing regulatory roles in signaling pathways that control cell proliferation and differentiation. HSPs also have a crucial role in activating client proteins within cells [6]. They have also been found to help in membrane stabilization and protein refolding under stressed conditions [7]. They also help to eliminate damaged or old cells under stress conditions to restore cellular homeostasis [8,9].
Cellular stress includes elevated temperature, reduced oxygen availability, ischemic conditions, and exposure to harmful substances, pathogens, ultraviolet (UV) radiation, or inflammatory signaling molecules. Exposure of organisms to pathophysiological, metabolic, or environmental stress conditions leads to the selective upregulation of HSPs as a natural cellular defense response [10]. This elevated expression of HSPs helps cells resist and thus acts via cytoprotective mechanisms [11].

2. HSP-Based Vaccines and Cancer Immunotherapy

HSPs function as chaperones within cells and bind to antigens (peptides) associated with tumors. Moreover, APCs can recognize complexes formed by HSPs and peptides, leading to specific antitumor responses [39]. HSPs play a role in enhancing immune responses during the presentation of tumor antigens. Consequently, there is evidence suggesting that immunization with HSPs obtained from tumor cells can elicit an immune response against the tumor [212]. Various members of the HSP chaperone families, connected with diverse cancer-peptide-based antigens, may be isolated from tumor cells. By purifying the heat-shock-protein–peptide groups/complexes from a patient’s isolated cancer, this complex can serve as a personalized tumor vaccine that delivers antigens derived from tumor cells to the immune system, thereby fostering anticancer immunity [213].
Scientific evidence on the link between HSPs and cancer vaccination has been supported by various studies. Chen et al. recently developed a vaccine composed of fusion proteins such as HSP65 and a peptide (octa) epitope from the six transmembrane epithelial antigens of the prostate 1 (STEAP1) [214]. STEAP1 is highly expressed in multiple types of cancers. The fusion protein HSP65/STEAP1 demonstrated the ability to inhibit or arrest B16F10 melanoma growth (xenograft) and mouse RM-1 prostate cancer [215]. Furthermore, His-HSP65 (HHSP65), a fusion protein, stimulates the expression of TNF-α and facilitates STEAP1 to enhance TNF-α secretion, effectively inhibiting cancer cell proliferation [216]. When combined with IFN-γ, TNF-α triggers the upregulation of MHC-II expression, initiating cellular immune responses and amplifying the cytotoxic activity of various immune cells. Moreover, a vaccine targeting the CD133 epitope coupled with an adjuvant such as gp96 facilitated the transfer of epitope-specific cytotoxic T lymphocytes (CTLs), effectively suppressing leukemia growth in a murine xenograft model [217]. Immunization with bone-marrow-derived dendritic cells derived from bone marrow (BMDCs) stimulated by placental gp96 resulted in reduced tumor growth and enhanced survival in mice. This approach elicits a robust tumor-specific T-cell response, establishing its efficacy as an immunotherapeutic strategy [218].
Recent clinical assessments have broadened the investigation of cancer immunotherapy utilizing HSP-based vaccines. A newly developed self-assembled nanochaperone inspired by HSPs has the potential to significantly augment cancer immunotherapy. This nano-vaccine employs HSP-like microdomains and mannose surface decoration to capture antigens, facilitating their movement into dendritic cells [219]. This process promotes the escape of antigens and improves their cross-presentation in the cytoplasm. This approach has demonstrated its capacity to stimulate responses from the immune system, including both CD8+ T cells (cytotoxic cells) and CD4+ T cells (helper cells), for the prevention of melanoma [219]. The combination of chaperone protein immunotherapy with checkpoint inhibitors of the immune system, such as anti-PD-1/PD-L1, is particularly emphasized in the treatment of melanoma [220].
Furthermore, clinical trials recorded on ClinicalTrials.gov have assessed the effectiveness of a combined intramuscular (IM) vaccination regimen involving pNGVL4a-Sig/E7(detox)/HSP70 DNA and singular intramuscular immunization with TA-CIN to promote clearance of human papillomavirus 16 (ClinicalTrials.gov Identifier: NCT03911076) [221]. Another set of trials investigated the GP96 HSP-peptide complex vaccine as a potential treatment for patients with liver cancer (ClinicalTrials.gov Identifier: NCT04206254) [222].
Glioblastoma, a primary brain cancer with poor or substantial prognosis, is under investigation for its effectiveness [223]. Standard therapy combined with HSPPC96-based vaccination has shown safety and efficacy in patients diagnosed with glioblastoma. TSIR, known as the tumor-specific immune response, predicts the vaccine’s efficacy, with high TSIR correlating with a median overall survival exceeding 40.5 months [224]. Further studies involve the sequencing of T-cell receptors to analyze the T-cell receptor repertoire in tumor-infiltrating lymphocytes (TILs) and identify potential biomarkers for predicting responses to HSPPC96 vaccination [225]. Additionally, a phase II trial in glioblastoma patients (adults) undergoing surgical resection following standard therapy and autologous HSP peptide vaccine (Prophage) administration revealed MGMT promoter methylation as a prognostic factor, with significantly extended overall median survival for methylated tumors compared to unmethylated tumors [226].

3. Photothermal and Modulated Electro-Hyperthermia Therapy

Emerging treatments for cancer include photothermal therapy (PTT) and modulated electro-hyperthermia therapy (mEHT). Both approaches to selectively target and eliminate malignant cells involve intentionally raising the temperature, which is referred to as hyperthermia. PTT mostly uses light-absorbing substances, usually nanoparticles. These substances absorb light energy at a certain wavelength and turn it into heat, which raises the temperature in the area, causing localized hyperthermia and damaging or killing cancer cells. Modulated electro-hyperthermia therapy is another form of hyperthermia therapy that involves the application of modulated electric fields to precisely elevate the temperature of cancer cells. Owing to their higher conductivity, cancer cells can consume a larger quantity of energy and experience higher temperatures than normal cells. However, the major problem associated with hyperthermia is the rapid expression of HSPs. However, the main problem with hyperthermia is that it causes rapid production and release of HSPs, which help proteins float inside cells and increase their tolerance [227]. The therapeutic efficacy of PTT is directly influenced by intracellular HSP expression levels, which have both protective and detrimental effects on cancer cells. Thus, the efficacy of hyperthermia therapy can be increased by inhibiting HSPs, which can reduce the thermal resistance of cancer cells and potentiate the cell-killing effect of hyperthermia [228]. Currently, HSP inhibitors are being used in combination with hyperthermia. For instance, Kuo et al. reported that mEHT increased efficiency by combining with the HSP inhibitors nano-curcumin and resveratrol in an in vivo CT26/BALB/c animal tumor model caused by decreased HSP70 expression and the infiltration of immune cells (CD3+ T-cells and F4/80+ macrophages) into tumors receiving this treatment [229].

4. Role of Chaperone-Mediated Autophagy in Cancer Diseases

Chaperone-mediated autophagy (CMA) primarily focuses on the degradation of misfolded proteins by translocating these polypeptides across the lysosomal membrane, thereby helping to maintain cellular homeostasis. There are reports on the dual nature of CMA in cancer because of its protumorigenic and antitumorigenic potential [230]. In a pro-tumorigenic role, CMA helps to survive and grow cancer cells through the modulation of the cell cycle. Hypoxia is an important characteristic observed in the tumor microenvironment, which helps activate CMA gene transcription. This CMA assists cancer survival and progression in the hypoxic microenvironment of tumors by hypoxia-inducible factor-1 alpha (HIF-1α) degradation (2). Similarly, the anti-oncogenic role or tumor-suppressive potential of CMA has been reported in the tumor microenvironment, where CMA is involved in protooncogene proteins such as Murine Double Minute 2 (MDM2) and tumor-associated translationally controlled tumor protein (TCTP) upon acetylation [231,232]. Although research in the field of CMA is still being conducted to examine the connection between faulty CMA and cancer, the translation of these results into preventative or therapeutic measures has been hampered by several issues. In the initial stage, every component and modulator of CMA, such as signaling elements and chaperones, participates in a wide range of crucial cellular processes. To date, no research has been conducted to identify a particular component of the CMA pathway that may be used as a target for external manipulation. This significant barrier must be overcome to discover selective chemical modulators of CMA. For instance, LAMP2A knockdown by direct injection of shRNA results in tumor regression and reduced metastasis in human lung cancer xenograft mice [233].

This entry is adapted from the peer-reviewed paper 10.3390/cancers16030638

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