Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: role of HSP70/TLR2/NF-kB axis
Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and
represent an important mode of intercellular communication. The ability of anticancer chemotherapy to
enhance the immunogenic potential of malignant cells mainly relies on the establishment of the
immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here,
we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma
(MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of
the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show
that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome
release from MM cells. MM cell-derived exosomes are capable of stimulating IFNg production, but not the
cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/
HSP70-dependent manner. Interestingly, HSP70 positive exosomes are primarily found in the bone marrow (BM)
of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor
microenvironment. We also provide evidence that the CD56high NK cell subset is more responsive to
exosome-induced IFNg production mediated by TLR2 engagement. All together, these findings suggest a
novel mechanism of synergism between chemotherapy and antitumor innate immune responses based
on the drug-promotion of nanovesicles exposing DAMPs for innate receptors
