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.

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

“…These include structural (cytoskeletal) proteins (i.e., actin, tubulin, and proteins associated with them) (Wubbolts et al, 2003), as well as proteins involved in trafficking of early and late endosomes and exosomes (e.g., Rabs, Tsg101, Alix) (Liang et al, 2013). Exosomes are also generally enriched with heat shock proteins and chaperones, represented by Hsp70 and Hsp90 (Chalmin et al, 2010). Exosomes originating from immune cells routinely carry a host of immunoregulatory proteins, such as cytokines (e.g., TNF-α, IL-1, IL-18, etc.)…”

Microenvironnement tumoral

“…Chez la souris, les exosomes issus de la tumeur activent la voie TLR2/MyD88 (myeloid differentiation primary response 88) dans les MDSC, induisant une production d'IL-6 par ces dernières. Cette IL-6 agit de manière autocrine sur les MDSC et induit la phosphorylation de Stat3, qui relaye l'activité immunosuppressive des MDSC [32]. L'IL-6 agit aussi sur les lymphocytes Th17, en influençant l'expression à leur surface des ectonucléotidases CD39 et CD73, qui jouent un rôle essentiel dans l'immunosuppression via leur production d'adénosine [18].…”

Cellules myéloïdes suppressives et cancer : une nouvelle cible thérapeutique

“…Rôle des facteurs dérivés de la tumeur sur les MDSC Dans une étude récente, nous avons recherché l'origine de l'activation des fonctions immunosuppressives des MDSC [7]. Est-elle induite par des facteurs solubles ou par les exosomes produits par les cellules cancéreuses ?…”