Introduction: The composition of the tumor microenvironment in HNSCC is associated with the immunological situation and therapy response, whereas exosomes are an important part of this regulatory network. As extracellular vesicles they are involved in the intercellular communication by transferring proteins and nucleic acids. We investigated the cellular characteristics and polarization of circulating monocytes and macrophages with regard to plasma and exosome associated factors in head and neck cancer patients, also in view of radio(chemo)therapeutic treatment. Methods: Expression CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and PD-L1 were investigated upon radio(chemo)therapeutic treatment using flow cytometry. Exosomes were isolated from plasma of healthy donors and HNSCC patients and evaluated regarding morphology, size and protein composition via transmission electron microscopy, nanoparticle tracking, western blot analysis and cytokine assays. Cytokine secretion patterns were analyzed by human cytokine antibody arrays and ELISA. Results: Our data reveal a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment and a significant correlation of monocytic checkpoint molecule PD-L1 with plasma chemokine CXCL11 (C-X-C motif chemokine 11). Furthermore, a significant type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from HNSCC patients, which could be visualized by fluorescence microcopy of membrane stained exosomes. Conclusions: The study provides new insights regarding tumor associated immune regulation via soluble and exosome related circulating mediators.

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