Increasing evidence has shown that extracellular vesicles play a relevant role in intercellular communication, thanks to their ability to convey active biological molecules onto target cells. Notably, a number of studies demonstrated that cancer derived-EVs have the capability to modulate both innate and adaptive immune responses thus contributing to influence tumor progression. Natural killer (NK) cells are innate lymphoid cells that play a major role in the immune surveillance against tumors and their activity is regulated through signals derived by a number of NK cell inhibitory and activating receptors as well as cytokines and other soluble factors released in the tumor microenvironment. NKG2D is an activating receptor expressed on the surface of NK cells, CD8+ ¿ß T lymphocytes, ¿¿ T cells, and NKT cells. It recognizes two families of ligands in human: MIC (MICA/B) and the ULBP (ULBP1-6) that are expressed on cell surface as signal of stress, as for example after viral infection or tumor transformation or in response to chemotherapy. Of note, NKG2D ligands (NKG2DLs) can be released in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle (EV) secretion. Focusing on multiple myeloma (MM) as a clinically and biologically relevant model of tumor-NK cell interactions, we found enrichment of EVs expressing MICA in the bone marrow of a cohort of patients. In this project we will investigate the immunomodulatory properties of the NKG2D ligand MICA associated to distinct populations of EVs (i.e exosomes and microvesicles). In sum, understanding the mechanisms by which NKG2D ligand associated to EVs influence the NK cell phenotype and functions can open new possibilities for cancer therapy.
Extracellular vesicles play a relevant role in intercellular communication, thanks to their ability to convey active biological molecules onto target cells (Colombo et al., 2014). Modulation of NK cell activity by exosomes appears to be multi-faceted and dependent on the identity of both the exosomes-associated cargo and exosome-releasing cells (Soriani et al., 2020); as such, a number of studies have described either inhibition or activation of NK cell-mediated functions (Borrelli et al., 2018; Clayton et al., 2008; Daßler-Plenker et al., 2016, Vulpis et al., 2017). There is increasing evidence that demonstrates the existence of various types of extracellular vesicles often having shared biophysical characteristics (Mathieu et al., 2019). The capability of cancer-derived EVs to carry immunomodulatory molecules represents a crucial aspect in the anti-tumor immune response, although further studies are necessary to evaluate the in vivo role of cancer-derived EVs. Our study will be focused on two main vesicle populations, namely exosomes comprising small extracellular vesicles ( Interestingly, specific receptor-targeting of extracellular vesicle surface represents a promising strategy to be used in cancer nanomedicine (Zocchi et al., 2020). Furthermore, various molecules have been described to contribute to interaction between EVs and target cells, including integrins, immunoglobulins, proteoglycans, lectins, and the T cell immunoglobulin and mucin domain-containing protein 4 (Tim4). These interactions appear to facilitate the endocytosis process and are important to define the selectivity of target cells (Mathieu et al., 2019). In this scenario, this project could offer an important tool to design and synthetize immunostimulatory nanoparticles carrying the NKG2D ligand MICA and targeting NKG2D expressing immune cells. To this regard, the production of synthetic nanoparticles mimicking exosome lipid composition (Caracciolo et al., 2017) and expressing immunomodulating molecules may represent an important way to promote the NK cell battle against cancer.