title: Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer.
abstract: 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.
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Jessica
authors.initials: J
authors.lastname: Gobbo
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcion
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Marine
authors.initials: M
authors.lastname: Cordonnier
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Alexandre M M
authors.initials: AMM
authors.lastname: Dias
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pernet
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Arlette
authors.initials: A
authors.lastname: Hammann
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Sarah
authors.initials: S
authors.lastname: Richaud
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Hajare
authors.initials: H
authors.lastname: Mjahed
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Victor
authors.initials: V
authors.lastname: Clausse
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bertaut
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Vincent
authors.initials: V
authors.lastname: Goussot
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lirussi
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Thonel
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Renaud
authors.initials: R
authors.lastname: Seigneuric
authors.affiliation: Affiliations of authors:INSERM, UMR 866, Laboratoire d'Excellence LipSTIC , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Faculty of Medicine and Pharmacy, University of Burgundy , Dijon , France (JG, GM, MC, AMMD, NP, AH, SR, HM, NI, VC, CR, FL, FG, AdT, RS, CG); Department of Medical Oncology, Georges-François Leclerc Centre , Dijon , France (JG, NI, CR, AB, VG, FG, PF, CG); Department of Biostatistics, Georges-François Leclerc Centre , Dijon , France (AB); CHU , Dijon , France (FL); Equipe Labellisée par la Ligue Nationale contre le Cancer (CG).
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052158:Aptamers, Peptide / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology*; D055354:Exosomes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007368:Interferometry / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D013154:Spleen; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052158:Aptamers, Peptide; D018840:HSP70 Heat-Shock Proteins; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2