[en] BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition.
Disciplines :
Oncology
Author, co-author :
Gobbo, Jessica; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Marcion, Guillaume ; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Cordonnier, Marine; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Dias, Alexandre M M; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Pernet, Nicolas; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Hammann, Arlette; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Richaud, Sarah; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Mjahed, Hajare; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Isambert, Nicolas; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Clausse, Victor; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Rébé, Cédric; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Bertaut, Aurélie; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Goussot, Vincent; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Lirussi, Frédéric; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Ghiringhelli, François; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
de Thonel, Aurélie; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Fumoleau, Pierre; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Seigneuric, Renaud; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
Garrido, Carmen; Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon
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