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

JNCI : Journal of the National Cancer Institute, 2016-03, Vol.108 (3), p.djv330 [Peer Reviewed Journal]

The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 0027-8874 ;ISSN: 1460-2105 ;EISSN: 1460-2105 ;DOI: 10.1093/jnci/djv330 ;PMID: 26598503

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Title:
Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer
Author: Gobbo, Jessica ; Marcion, Guillaume ; Cordonnier, Marine ; Dias, Alexandre M M ; Pernet, Nicolas ; Hammann, Arlette ; Richaud, Sarah ; Mjahed, Hajare ; Isambert, Nicolas ; Clausse, Victor ; Rébé, Cédric ; Bertaut, Aurélie ; Goussot, Vincent ; Lirussi, Frédéric ; Ghiringhelli, François ; de Thonel, Aurélie ; Fumoleau, Pierre ; Seigneuric, Renaud ; Garrido, Carmen
Subjects: Animals ; Antineoplastic Agents ; Antineoplastic Agents - pharmacology ; Aptamers, Peptide ; Aptamers, Peptide - metabolism ; Breast Neoplasms - drug therapy ; Breast Neoplasms - immunology ; Breast Neoplasms/drug therapy/immunology ; Cancer ; Cell Line, Tumor ; Cell Proliferation ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - immunology ; Colonic Neoplasms/drug therapy/immunology ; Exosomes - drug effects ; Exosomes - immunology ; Exosomes/drug effects/immunology ; Female ; HSP70 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins - metabolism ; Human health sciences ; Humans ; Interferometry - methods ; Life Sciences ; Lung Neoplasms - drug therapy ; Lung Neoplasms - immunology ; Lung Neoplasms/drug therapy/immunology ; Lymphocytes, Tumor-Infiltrating - immunology ; Male ; Mice ; Mice, Inbred C57BL ; Myeloid Cells - immunology ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - immunology ; Neoplasms, Experimental/drug therapy/immunology ; Oncologie ; Oncology ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms/drug therapy/immunology ; Sciences de la santé humaine ; Spleen ; TLR2 protein, human ; Tlr2 protein, mouse ; Toll-Like Receptor 2 ; Toll-Like Receptor 2 - metabolism
Is Part Of: JNCI : Journal of the National Cancer Institute, 2016-03, Vol.108 (3), p.djv330
Description: Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them. We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy. Data were analyzed with the Student's t and Mann-Whitney tests. All statistical tests were two-sided. We showed that the A8 peptide aptamer binds to the extracellular domain of membrane HSP70 and used the aptamer to capture HSP70 exosomes from cancer patient samples. The number of HSP70 exosomes was higher in cancer patients than in healthy donors (mean, ng/mL ± SD = 3.5 ± 1.7 vs 0.17 ± 0.11, respectively, P = .004). Accordingly, all cancer cell lines examined abundantly released HSP70 exosomes, whereas "normal" cells did not. HSP70 had higher affinity for A8 than for TLR2; thus, A8 blocked HSP70/TLR2 association and the ability of tumor-derived exosomes to activate MDSCs. Treatment of tumor-bearing C57Bl/6 mice with A8 induced a decrease in the number of MDSCs in the spleen and inhibited tumor progression (n = 6 mice per group). Chemotherapeutic agents such as cisplatin or 5FU increase the amount of HSP70 exosomes, favoring the activation of MDSCs and hampering the development of an antitumor immune response. In contrast, this MDSC activation was not observed if cisplatin or 5FU was combined with A8. As a result, the antitumor effect of the drugs was strongly potentiated. A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition.
Publisher: United States: Oxford University Press (OUP)
Language: English
Identifier: ISSN: 0027-8874
ISSN: 1460-2105
EISSN: 1460-2105
DOI: 10.1093/jnci/djv330
PMID: 26598503
Source: GFMER Free Medical Journals
MEDLINE
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Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer

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