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Exosomes are endosome-derived nanovesicles involved in intercellular cross-talk through
the transfer of proteins and genetic material. In cancer, exosomes can contribute
to mould host micro- and macroenvironment, conditioning tumour immunity both at local
and systemic level. We have been collecting evidence that these nanovesicles exert
a broad array of detrimental effects on the immune system, ranging from apoptosis
in activated antitumour T cells to impairment of monocyte differentiation into dendritic
cells and induction of suppressive effectors. More recently, we observed that cells
with phenotypic and functional properties overlapping with those displayed by myeloid-derived
suppressor cells (MDSC) can be generated in vitro by culturing normal monocytes with exosomes released by melanoma cells (Exo-MDSC).
Compared to untreated monocytes, Exo-MDSC show increased mRNA level and release of
protumourigenic and immunosuppressive cyto/chemokines, down-modulate the expression
of HLA-DR and TLRs, and acquire the ability to inhibit T cell proliferation. A defined
gene-expression and miRNA signature, involving HIF1alfa, IL6 and several immune-related
genes, has been identified in Exo-MDSC as triggered by exosomal TGFb, CCL2 and selected
miRNA.
Given their ability to efficiently recirculate in body fluids, tumour exosomes could
spread systemically and directly condition myelopoiesis. This hypothesis is supported
by the evidence that peripheral MDSC from melanoma patients share defined traits of
Exo-MDSC gene-expression and miRNA signature, in addition with phenotypic and functional
features of these cells. MDSC accumulate in peripheral blood of melanoma patients
as an early event and in association with disease progression. High MDSC frequency
is an acknowledged negative prognostic factor in several tumour histologies and predicts
poor response to immunotherapy, including checkpoint blockade. The identification
of exosomes as a potential pathway responsible for MDSC mobilisation and accrual paves
the way to the development of novel immune-based therapeutic strategies and prognostic
biomarkers in cancer patients.
Supported by Italian Association For Cancer Research – AIRC Grant code 12162.
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