Tumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution

Abstract

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.

Cytokine Profiling in Low- and High-Density Small Extracellular Vesicles from Epidermoid Carcinoma Cells

“…In cancer, cytokines can promote tumor cell growth, migration, and metastasis, or as immunoregulators, they can create a microenvironment favorable for tumor growth by stimulating the infiltration of the immunosuppressive myeloid-derived suppressor cells ( Taki et al., 2018 ; Umansky et al., 2016 ). Recent studies suggest that these cytokines may, in fact, associate with the surface of sEVs by binding to surface proteoglycans, which is essential for sEV‒cell interactions ( Fitzgerald et al., 2018 ; Lima et al., 2021 ). However, it is not known whether these cytokines are differentially associated with subpopulations of sEVs.…”

Organ-specific uptake of extracellular vesicles secreted by urological cancer cells

“…One explanation is the different distribution of surface molecules on the membrane of extracellular vesicles, which are involved in receptormediated uptake. Here, for example, integrins could be shown to be involved [9,12], as were cytokines [34], CD47 [35], and surface glycans [36]. Apart from that, the size of the EVs, the vascularization and microenvironment of the target organ, and the order in which the single organs are passed by the injected EVs are other possible factors influencing their uptake [29].…”

Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

“…Other factors that influence EV biodistribution and uptake in vivo is the microenvironment from which they are released. Tumor-derived EVs can bind to soluble secreted cytokines and chemokines (i.e., CCL2 and IL-6) in the tumor microenvironment through their surface-expressed glycosaminoglycan (GAG) side chains of proteoglycans, significantly increase their uptake in the liver, spleen, and lung ( Lima et al, 2021 ). Through a similar mechanism, EVs expressing GAGs released by glioblastoma bind to, and are decorated with, chemokine ligand CCL18, facilitating their interaction with cognate receptor CCR8 on recipient glioblastoma cells ( Berenguer et al, 2018 ) to increase uptake and induce a proliferative phenotype ( Berenguer et al, 2018 ).…”