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

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms20184588 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4588 ◽

Cited By ~ 23

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.

Download Full-text

Current Applications and Discoveries Related to the Membrane Components of Circulating Tumor Cells and Extracellular Vesicles

Cells ◽

10.3390/cells10092221 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2221

Author(s):

Luis Enrique Cortés-Hernández ◽

Zahra Eslami-S ◽

Bruno Costa-Silva ◽

Catherine Alix-Panabières

Keyword(s):

Nucleic Acids ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Liquid Biopsy ◽

Clinical Information ◽

Phospholipid Membrane ◽

Membrane Composition ◽

Metastatic Cascade

In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.

Download Full-text

Cancer associated-fibroblast-derived exosomes in cancer progression

Molecular Cancer ◽

10.1186/s12943-021-01463-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Chao Li ◽

Adilson Fonseca Teixeira ◽

Hong-Jian Zhu ◽

Peter ten Dijke

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Chemotherapy Resistance ◽

Cell Types ◽

Cancer Therapies ◽

Cancer Associated Fibroblast

AbstractTo identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Download Full-text

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

Cancers ◽

10.3390/cancers13112638 ◽

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.

Download Full-text

Checkpoint Inhibitors and Hepatotoxicity

Biomedicines ◽

10.3390/biomedicines9020101 ◽

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.

Download Full-text

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

10.1101/633560 ◽

2019 ◽

Cited By ~ 1

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.

Download Full-text

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

Cell Death and Differentiation ◽

10.1038/s41418-020-00686-8 ◽

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.

Download Full-text

Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools

Diagnostics ◽

10.3390/diagnostics10121065 ◽

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.

Download Full-text

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

Journal of Clinical Medicine ◽

10.3390/jcm9113529 ◽

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.

Download Full-text

Exosomes in Immune Regulation

Non-Coding RNA ◽

10.3390/ncrna7010004 ◽

2021 ◽

Vol 7 (1) ◽

pp. 4

Author(s):

Heidi Schwarzenbach ◽

Peter B. Gahan

Keyword(s):

Immune System ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Cells ◽

Intercellular Communication ◽

Immune Regulation ◽

Immune Escape ◽

Cytotoxic Responses

Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor.

Download Full-text