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Membrane-associatedHsp72 fromtumor-derivedexosomes mediatesSTAT3-dependentimmunosuppressivefunction of mouse andhuman myeloid-derivedsuppressor cells Fanny ChalminSylvain LadoireGrégoire Mignot2010 год

Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
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Аннотация: Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
Год издания: 2010
Авторы: Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Julie Vincent, Mélanie Bruchard, Jean-Paul Rémy-Martin, Wilfrid Boireau, Alain Rouleau, B. Simon, David Lanneau, Aurélie de Thonel, Gabriele Multhoff, Arlette Hamman, François Martin, Bruno Chauffert, Éric Solary, Laurence Zitvogel, Carmen Garrido, Bernhard Ryffel, Christophe Borg, Lionel Apétoh, Cédric Rébé, François Ghiringhelli
Издательство: American Society for Clinical Investigation
Источник: Journal of Clinical Investigation
Ключевые слова: Heat shock proteins research, Viral gastroenteritis research and epidemiology, Extracellular vesicles in disease
Другие ссылки: Journal of Clinical Investigation (PDF)
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Europe PMC (PubMed Central) (PDF)
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PubMed Central (HTML)
HAL (Le Centre pour la Communication Scientifique Directe) (HTML)
HAL (Le Centre pour la Communication Scientifique Directe) (PDF)
HAL (Le Centre pour la Communication Scientifique Directe) (HTML)
HAL (Le Centre pour la Communication Scientifique Directe) (HTML)
HAL (Le Centre pour la Communication Scientifique Directe) (PDF)
HAL (Le Centre pour la Communication Scientifique Directe) (HTML)
PubMed (HTML)