Induction of myeloid‐derived suppressor cells by tumor exosomes

Abstract

Myeloid‐derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T‐exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T‐exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b+Gr‐1+). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T‐exosome prostaglandin E2 (PGE2) and TGF‐β molecules. T‐exosomes can induce the accumulation of MDSCs expressing Cox2, IL‐6, VEGF, and arginase‐1. Antibodies against exosomal PGE2 and TGF‐β block the activity of these exosomes on MDSC induction and therefore attenuate MDSC‐mediated tumor‐promoting ability. Exosomal PGE2 and TGF‐β are enriched in T‐exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C‐exosomes). The tumor microenvironment has an effect on the potency of T‐exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF‐β available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC‐induced immunosuppression and hence enhance host antitumor immunotherapy efficacy. © 2008 Wiley‐Liss, Inc.

The exosomes in tumor immunity

“…[25][26][27] Moreover, mice pretreated with TEXs also showed an accumulation of MDSCs in spleen, peripheral blood and lung. 28 Interestingly, heat shock protein 72 (HSP72) expressed at the surface of TEXs could induce activation of Stat3 and production of IL-6 in a TLR2/MyD88-dependent manner, thus promoting suppressive functions of MDSCs. 29 Furthermore, TEXs could be uptaken by immature DCs and then block DC maturation.…”

Exosomes as intercellular signalosomes and pharmacological effectors

“…It was shown that melanoma and colorectal carcinoma-derived exosomes altered the monocyte differentiation into dendritic cells, leading to the generation of myeloid suppressive cells [94]. Furthermore, it was demonstrated that MDSC-mediated promotion of tumor progression was dependent on TGF- present on exosomes, but also depended upon the lipidic mediator prostaglandin E2 (PGE2) transported by tumor exosomes [95].…”

“…Results on prostaglandins were obtained on exosomes released from a rat basophil leukemia cell line (RBL-2H3) [9], and it is required to screen more tumor-derived exosomes to assess whether the prostaglandin profile of exosomes could account for tumorprogression in-vivo. It is worth to note that incubating tumor exosomes with anti-PGE2 antibody decreases their effect on myeloid-derived suppressor cell expansion [95].…”

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…7,13 MDSCs are a heterogeneous population of bone marrow-derived myeloid progenitors and immature myeloid cells that expand dramatically during tumor growth, leading to an increased proportion of MDSCs in the peripheral blood and tumor microenvironments of cancer patients. 14,15 The MDSC phenotype varies by differentiation status and function in response to the environmental conditions of different cancers and generally has been termed as the HLA-DR ¡ CD33 C CD11b C cell population, including PMN-and MO-MDSCs, in many human cancers. [16][17][18][19] In humans, these tumor-associated MDSCs have drawn attention due to their role in tumor progression.…”