Renaud Seigneuric

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.

Scientific advances have significantly improved the practice of medicine by providing objective and quantitative means for exploring the human body and disease states. These innovative technologies have already profoundly improved disease detection, imaging, treatment and patient follow-up. Todays analytical limits are at the nanoscale level (one-billionth of a meter) enabling a detailed exploration at the level of DNA, RNA, proteins and metabolites which are in fact nano-objects. This translational review aims at integrating some recent advances from micro- and nano-technologies with high potential for improving daily oncology practice. Keywords: Nanomedicine, circulating tumour cell, nanoparticle, EPR effect, Nanotechnology, Enzymes, Antibodies, Blood-brain barrier, Nano-objects, Nanospheres, Nanotubes, Nanorods, Nanowires, Biosensors, Biomolecules, Biomarkers, Metastases, Clonogenic cancer cells, Epithelial Cell Adhesion Molecule, EpCAM(CD326), Antigen, Antibody, immunohistochemistry, Fluorescence microscope, CTC chip, Aptamers, Aptasensors, Nanovectorization, Surface plasmon resonance, Ellipsometry, SPR imaging, Microfluidics, Microtechnologies, Electrophoresis, ELISA, Labs-on-chip, Point-of-care devices, Drug delivery, Radiotherapy, Chemotherapy, Pharmacokinetics, Reticuloendothelial system, Immune system, Nanoparticles, Vectorization, Doxorubicin, Anthracyclins, Cardiotoxicity, Myelosuppression, Paclitaxel, Docetaxel, DNA topoisomerase, XMT-1001, Camptothecin, Tumor necrosis, Factor alpha, Reactive oxygen species