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

被引:159
作者
Gobbo, Jessica [1 ,2 ,3 ]
Marcion, Guillaume [1 ,2 ]
Cordonnier, Marine [1 ,2 ]
Dias, Alexandre M. M. [1 ,2 ]
Pernet, Nicolas [1 ,2 ]
Hammann, Arlette [1 ,2 ]
Richaud, Sarah [1 ,2 ]
Mjahed, Hajare [1 ,2 ]
Isambert, Nicolas [1 ,2 ,3 ]
Clausse, Victor [1 ,2 ]
Rebe, Cederic [1 ,2 ,3 ]
Bertaut, Aurelie [3 ,4 ]
Goussot, Vincent [3 ]
Lirussi, Frederic [1 ,5 ]
Ghiringhelli, Francois [1 ,2 ,3 ]
de Thonel, Aurelie [1 ,2 ]
Fumoleau, Pierre [3 ]
Seigneuric, Renaud [1 ,2 ]
Garrido, Carmen [1 ,2 ,3 ,6 ]
机构
[1] INSERM, UMR 866, Lab Excellence LipSTIC, F-21079 Dijon, France
[2] Univ Burgundy, Fac Med & Pharm, Dijon, France
[3] Georges Francois Leclerc Ctr, Dept Med Oncol, Dijon, France
[4] Georges Francois Leclerc Ctr, Dept Biostat, Dijon, France
[5] CHU, Dijon, France
[6] Equipe Labellisee Ligue Natl Canc, Illkirch Graffenstaden, France
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2016年 / 108卷 / 03期
关键词
MEMBRANE HEAT-SHOCK-PROTEIN-70 HSP70; SUPPRESSOR-CELLS; CANCER; MACROPHAGES; MECHANISMS; PHENOTYPE; RELEASE;
D O I
10.1093/jnci/djv330
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页数:11
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