Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
Fanny Chalmin, … , Cédric Rébé, François Ghiringhelli
Fanny Chalmin, … , Cédric Rébé, François Ghiringhelli
Published January 19, 2010
Citation Information: J Clin Invest. 2010;120(2):457-471. https://doi.org/10.1172/JCI40483.
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Research Article Immunology

Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells

Abstract

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.

Authors

Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Julie Vincent, Mélanie Bruchard, Jean-Paul Remy-Martin, Wilfrid Boireau, Alain Rouleau, Benoit Simon, David Lanneau, Aurélie De Thonel, Gabriele Multhoff, Arlette Hamman, François Martin, Bruno Chauffert, Eric Solary, Laurence Zitvogel, Carmen Garrido, Bernhard Ryffel, Christophe Borg, Lionel Apetoh, Cédric Rébé, François Ghiringhelli

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Figure 7

Exosome depletion restores the efficacy of immunotherapy.

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Exosome depletion restores the efficacy of immunotherapy. Immunocompeten...
Immunocompetent mice (A) were injected s.c. with 1 × 106 CT26, TS/A, or EL4 cells. Mice were then either untreated or treated with 1 i.p. injection of 100 mg/kg cyclophosphamide (CTX), daily i.p. injection of DMA, or both. Mean tumor volume ± SD (n = 6 mice per group). (B) WT mice were injected as in A with CT26 and treated with intratumoral CpG 1668 injection (10 μg once a week) with or without DMA. (C) Nude mice were treated as in A. (D) BALB/c mice were injected s.c. with 1 × 106 CT26 cells. Mice were then either untreated or treated with 1 i.p. injection of cyclophosphamide or 1 i.p. injection of cyclophosphamide plus repeated daily i.p. injections of DMA with or without an i.v. adoptive transfer of 5 × 106 MDSCs from CT26 tumor-bearing mice. Data shown represent mean tumor volume ± SD (n = 5 mice per group). (E) BALB/c mice were injected s.c. with 1 × 106 mock-transfected (left panel) or Hsp72 shRNA–transfected (clone H96, middle panel; clone H97, right panel) CT26 cells. Mice were then either untreated or treated with 1 i.p. injection of cyclophosphamide, i.p. injection of DMA twice a week, or both. Mean tumor volume ± SD (n = 6 mice per group). Experiments were performed in duplicate. *P < 0.05.