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

2019 ◽  
Vol 20 (18) ◽  
pp. 4588 ◽  
Author(s):  
Eman A. Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Membrane Surface ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Heterochromatin Protein 1 ◽  
Liquid Biopsies

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.

scholarly journals Roles of Extracellular Vesicles (EVs) Carrying HSPs in Cancer Biomarkers, Immune Surveillance, and Immune Evasion

2019 ◽  
Author(s):  
Eman Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Targeted Therapeutics ◽  
Heterochromatin Protein 1

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

scholarly journals Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2638
Author(s):  
Vito Amodio ◽  
Gianluca Mauri ◽  
Nicole M. Reilly ◽  
Andrea Sartore-Bianchi ◽  
Salvatore Siena ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Evasion ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Clinical Samples ◽  
Primary Resistance ◽  
Mechanistic Basis ◽  
Sting Pathway ◽  
Beta 2 Microglobulin

Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

scholarly journals Checkpoint Inhibitors and Hepatotoxicity

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 101
Author(s):  
Stephen D. H. Malnick ◽  
Ali Abdullah ◽  
Manuela G. Neuman
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Transforming Growth Factor Β ◽  
Antigenic Modulation ◽  
Growing Cell ◽  
The Individual ◽  
Drug Interventions

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. Tumor cells escape the immune surveillance mechanism, avoiding immune detection and elimination by activating these checkpoints and suppressing the anti-tumor response, thus allowing formation of tumors. Antigenic modulation facilitates masking and contributes to the escape of tumor cells. In addition, there are growing cell promoters, like transforming growth factor β (TGF-β), contributing to escape mechanisms. Targeting the immunological escape of malignant cells is the basis of immune oncology. Checkpoint inhibitors, cytokines and their antibodies may enhance the immune system’s response to tumors. Currently, immunomodulatory agents have been designed, evaluated in clinical trials and have been approved by both European and United States Drug Agencies. The present review is a reflection of the increasingly important role of the checkpoint inhibitors. Our aim is to review the side effects with the emphasis on hepatic adverse reactions of these novel biological drug interventions.

scholarly journals DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress in triplenegative breast cancer

2019 ◽  
Author(s):  
Rita Moreno ◽  
Sourav Banerjee ◽  
Angus W. Jackson ◽  
Jean Quinn ◽  
Gregg Baillie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heat Shock ◽  
Cancer Progression ◽  
Xenograft Model ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Proteotoxic Stress ◽  
Dual Specificity ◽  
Stress Response Pathway ◽  
Nuclear Stability

SummaryTo survive aneuploidy-induced proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive target. As developing HSF1 inhibitors is challenging, the identification and targeting of upstream regulators of HSF1 presents a tractable alternative strategy. Here we demonstrate that in triple negative breast cancer (TNBC) cells, the dual-specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. Thus, DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. In agreement with this, DYRK2 depletion reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, a key modulator of the HSF1 transcriptional program, and a potential therapeutic target.

scholarly journals The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress

2020 ◽  
Author(s):  
Rita Moreno ◽  
Sourav Banerjee ◽  
Angus W. Jackson ◽  
Jean Quinn ◽  
Gregg Baillie ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Proteotoxic Stress ◽  
Dual Specificity ◽  
Stress Response Pathway ◽  
Nuclear Stability ◽  
Attractive Therapeutic Target

AbstractTo survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.

scholarly journals Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1065
Author(s):  
Jihane Khalife ◽  
James F. Sanchez ◽  
Flavia Pichiorri
Keyword(s):  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Hematological Malignancies ◽  
Immune Surveillance ◽  
Therapeutic Targets ◽  
Molecular Signature ◽  
Response To Treatment ◽  
Clinical Tool ◽  
Liquid Biopsies ◽  
Disease Stratification

Small extracellular vesicles (EVs) are a heterogenous group of lipid particles released by all cell types in physiological and pathological states. In hematological malignancies, tumor-derived EVs are critical players in mediating intercellular communications through the transfer of genetic materials and proteins between neoplastic cells themselves and to several components of the bone marrow microenvironment, rendering the latter a “stronger” niche supporting cancer cell proliferation, drug resistance, and escape from immune surveillance. In this context, the molecular cargoes of tumor-derived EVs reflect the nature and status of the cells of origin, making them specific therapeutic targets. Another important characteristic of EVs in hematological malignancies is their use as a potential “liquid biopsy” because of their high abundance in biofluids and their ability to protect their molecular cargoes from nuclease and protease degradation. Liquid biopsies are non-invasive blood tests that provide a molecular profiling clinical tool as an alternative method of disease stratification, especially in cancer patients where solid biopsies have limited accessibility. They offer accurate diagnoses and identify specific biomarkers for monitoring of disease progression and response to treatment. In this review, we will focus on the role of EVs in the most prevalent hematological malignancies, particularly on their prospective use as biomarkers in the context of liquid biopsies, as well as their molecular signature that identifies them as specific therapeutic targets for inhibiting cancer progression. We will also highlight their roles in modulating the immune response by acting as both immunosuppressors and activators of anti-tumor immunity.

scholarly journals Optimization of rVAR2-Based Isolation of Cancer Cells in Blood for Building a Robust Assay for Clinical Detection of Circulating Tumor Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2401 ◽  
Author(s):  
Nicolai T. Sand ◽  
Tobias B. Petersen ◽  
Sara R. Bang-Christensen ◽  
Theresa D. Ahrens ◽  
Caroline Løppke ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Magnetic Beads ◽  
Liquid Biopsies ◽  
Blood Samples ◽  
Non Invasive ◽  
Clinical Detection

Early detection and monitoring of cancer progression is key to successful treatment. Therefore, much research is invested in developing technologies, enabling effective and valuable use of non-invasive liquid biopsies. This includes the detection and analysis of circulating tumor cells (CTCs) from blood samples. Recombinant malaria protein VAR2CSA (rVAR2) binds a unique chondroitin sulfate modification present on the vast majority of cancers and thereby holds promise as a near-universal tumor cell-targeting reagent to isolate CTCs from complex blood samples. This study describes a technical approach for optimizing the coupling of rVAR2 to magnetic beads and the development of a CTC isolation platform targeting a range of different cancer cell lines. We investigate both direct and indirect approaches for rVAR2-mediated bead retrieval of cancer cells and conclude that an indirect capture approach is most effective for rVAR2-based cancer cell retrieval.

scholarly journals A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment

2020 ◽  
Vol 9 (11) ◽  
pp. 3529
Author(s):  
Mihnea P. Dragomir ◽  
Vlad Moisoiu ◽  
Roxana Manaila ◽  
Barbara Pardini ◽  
Erik Knutsen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Systemic Disease ◽  
Improved Outcomes ◽  
Complex Landscape ◽  
Endothelial Growth Factor

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients.

scholarly journals Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3762
Author(s):  
Melissa Schwab ◽  
Katharina Thunborg ◽  
Omid Azimzadeh ◽  
Christine von Toerne ◽  
Caroline Werner ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Metabolism ◽  
Glucose Deprivation ◽  
Therapy Resistance ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Double Knockout ◽  
Ldh Activity

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH−/−) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.

scholarly journals An immunotherapeutic approach to decipher the role of long non-coding RNAs in cancer progression, resistance and epigenetic regulation of immune cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Krishnapriya M. Varier ◽  
Hemavathi Dhandapani ◽  
Wuling Liu ◽  
Jialei Song ◽  
Chunlin Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Specific Gene ◽  
Epigenetic Modifiers ◽  
Cancer Types ◽  
Suppression Of Immune Response ◽  
Non Coding Rnas

AbstractImmunotherapeutic treatments are gaining attention due to their effective anti-tumor response. Particularly, the revolution of immune checkpoint inhibitors (ICIs) produces promising outcomes for various cancer types. However, the usage of immunotherapy is limited due to its low response rate, suggesting that tumor cells escape the immune surveillance. Rapid advances in transcriptomic profiling have led to recognize immune-related long non-coding RNAs (LncRNAs), as regulators of immune cell-specific gene expression that mediates immune stimulatory as well as suppression of immune response, indicating LncRNAs as targets to improve the efficacy of immunotherapy against tumours. Moreover, the immune-related LncRNAs acting as epigenetic modifiers are also under deep investigation. Thus, herein, is a summarised knowledge of LncRNAs and their regulation in the adaptive and innate immune system, considering their importance in autophagy and predicting putative immunotherapeutic responses.

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