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

Luize G. Lima, Sunyoung Ham, Hyunku Shin, Edna P. Z. Chai, Erica S. H. Lek, Richard J. Lobb, Alexandra F. Müller, Suresh Mathivanan, Belinda Yeo, Yeonho Choi, Belinda S. Parker and Andreas Möller ()
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Luize G. Lima: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Sunyoung Ham: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Hyunku Shin: Korea University
Edna P. Z. Chai: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Erica S. H. Lek: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Richard J. Lobb: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Alexandra F. Müller: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute
Suresh Mathivanan: La Trobe Institute for Molecular Science, La Trobe University
Belinda Yeo: Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg
Yeonho Choi: Korea University
Belinda S. Parker: Peter MacCallum Cancer Centre
Andreas Möller: Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23946-8

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