Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer

Gobbo, Jessica; Marcion, Guillaume; Cordonnier, Marine; Dias, A.; Pernet, Nicolas; Hammann, Arlette; Richaud, Sarah; Mjahed, Hajare; Isambert, Nicolás; Clausse, Victor; Rébé, Cédric; Bertaut, Aurélie; Goussot, Vincent; Lirussi, Frédéric; Ghiringhelli, François; Thonel, Aurélie de; Fumoleau, P.; Seigneuric, Renaud; Garrido, Carmen

doi:10.1093/jnci/djv330

Cited by 172 publications

(161 citation statements)

References 33 publications

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“…Thereby, in vivo and in vitro, A8 induce the development of an efficient anti-tumor immune response that was associated to an inhibition of MDSC. 50 In line with our results proposing an HSP70 inhibitor -A8-as an agent that can boost the anti-cancer immune response, HSP90-exosomes have been described as to be involved in the activation of plasmin and cancer cells' motility in several cancer models. Thus, targeting HSP90 could also represent a way to limit tumor invasion by inhibiting a growing number of proteins that are involved in tumor cell motility.…”

Section: Hsp-exosomes In Cancer Therapysupporting

confidence: 83%

“…Exosomes have been reported to be involved in all stages in cancer development: (i) tumorigenic transformation, (ii) tumor growth, (iii) angiogenesis, (iv) modulation of immune responses, and (v) induction of mechanisms to acquire therapy resistance. [50][51][52][53] The impact of exosomes in clinical research is demonstrated by the fact that there are already 19 clinical trials ongoing (web site https://clinicaltrials.gov/). Among them, 13 involve the study of exosomes as cancer diagnosis biomarkers whereas the others use the exosomes for cancer therapy purposes.…”

Section: Clinical Interest Of Exosomes In Cancermentioning

confidence: 99%

“…We have shown that all cancer cells analyzed so far have the ability to secrete exosomes with HSP70 in their membrane while normal "non cancerous" cells do not. These tumor-derived exosomes, through membraneanchored HSP70, can activate Myeloid Derived Suppressor Cells (MDSCs), 121,50 which are abundant cells in a cancer context that restrain antitumor immunity and promote tumor expansion. At the molecular level, the extracellular domain of membrane HSP70 binds to the Toll-Like Receptor 2 at the surface of MDSCs thus activating them.…”

Section: Hsp-exosomes In Cancer Therapymentioning

confidence: 99%

“…Our team suggests the use of HSP70-exosomes as a cancer marker because they seem a general feature of cancer cells (but not of "normal" non-cancerous cells) and we have demonstrated that they can be measured in large amounts in biological fluids from cancer patients but not from healthy individuals where they are hardly detected. 50 We have patented an interference biolayer protocol to easily capture HSP70-exosomes isolated from human fluids using as a high affinity ligand our peptide aptamer A8 (WO2015/189395 131 ). To move beyond the proof of principle that these tumor-derived exosomes (HSP70-exosomes) can be quantified and might be interesting to follow up cancer patients, we have started a prospective study with the anticancer Center Georges-François Leclerc (CGFL, Dijon, France) in breast, ovarian and lung cancer aiming at determining whether the presence of HSP70-exosomes is predictive of the patients' outcome and whether their detection precedes CTCs and the apparition of metastases.…”

Section: Hsp-exosomes In Cancer Diagnosismentioning

confidence: 99%

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Exosomes in cancer theranostic: Diamonds in the rough

Cordonnier

Chanteloup

Isambert

et al. 2017

Cell Adhesion & Migration

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During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSPexosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.

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Section: Hsp-exosomes In Cancer Therapysupporting

confidence: 83%

Section: Clinical Interest Of Exosomes In Cancermentioning

confidence: 99%

Section: Hsp-exosomes In Cancer Therapymentioning

confidence: 99%

Section: Hsp-exosomes In Cancer Diagnosismentioning

confidence: 99%

See 2 more Smart Citations

Exosomes in cancer theranostic: Diamonds in the rough

Cordonnier

Chanteloup

Isambert

et al. 2017

Cell Adhesion & Migration

Self Cite

View full text Add to dashboard Cite

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“…43 The addition of the A8 peptide to the culture medium partially suppressed the induction of IFNg expression by MM cellderived exosomes, whereas a scrambled peptide had no effect (Fig. 7B), indicating that HSP70 expressed on the outer membrane of exosomes could contribute to TLR2 triggering in NK cells.…”

Section: Hsp70 Is Associated With Mm-derived Exosomes and Contributesmentioning

confidence: 93%

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

et al. 2017

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Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here, we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma (MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome release from MM cells. MM cell-derived exosomes are capable of stimulating IFNg production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/ HSP70-dependent manner. Interestingly, HSP70C exosomes are primarily found in the bone marrow (BM) of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor microenvironment. We also provide evidence that the CD56 high NK cell subset is more responsive to exosome-induced IFNg production mediated by TLR2 engagement. All together, these findings suggest a novel mechanism of synergism between chemotherapy and antitumor innate immune responses based on the drug-promotion of nanovesicles exposing DAMPs for innate receptors.

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The cancer exosomes: Clinical implications, applications and challenges

Tang

Hou

et al. 2019

Intl Journal of Cancer

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The exosome is a small functional vesicle enriched in selected proteins, lipids and nucleic acids, displaying distinct molecular heterogeneity. Exosomes released can transform the extracellular matrix microenvironments, transmit signals and molecules to recipient cells and trigger changes in their pathophysiological functions. Tumor‐derived exosomes mediate the interactions of tumor cells and microenvironment significantly, and they stimulate tumor growth and development through specific signaling pathways related to metastasis, therapeutic resistance and immunosuppression. Exosome biogenesis from tumors often represents abundant biological information, and novel and efficient isolation and detection methods of exosomes provide a promising approach for tumor diagnosis and prognosis estimation. Moreover, exosome can even be developed as therapeutic agents for multiple disease models based on effective material transport characteristics and biofilm specificity. This review reports the clinical implications and challenges of exosomes in cancer progression, therapy resistance, metastasis and immune escape, and underlying cancerogenic pathological phenotypes including fibrosis and viral infection.

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Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer

Abstract: A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition.

Cited by 172 publications

References 33 publications

Exosomes in cancer theranostic: Diamonds in the rough

Exosomes in cancer theranostic: Diamonds in the rough

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

The cancer exosomes: Clinical implications, applications and challenges

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