Diagnostic and Therapeutic Potential of Extracellular Vesicles in B-Cell Malignancies

Abstract

Extracellular vesicles (EV), comprising microvesicles and exosomes, are particles released by every cell of an organism, found in all biological fluids, and commonly involved in cell-to-cell communication through the transfer of cargo materials such as miRNA, proteins, and immune-related ligands (e.g., FasL and PD-L1). An important characteristic of EV is that their composition, abundance, and roles are tightly related to the parental cells. This translates into a higher release of characteristic pro-tumor EV by cancer cells that leads to harming signals toward healthy microenvironment cells. In line with this, the key role of tumor-derived EV in cancer progression was demonstrated in multiple studies and is considered a hot topic in the field of oncology. Given their characteristics, tumor-derived EV carry important information concerning the state of tumor cells. This can be used to follow the outset, development, and progression of the neoplasia and to evaluate the design of appropriate therapeutic strategies. In keeping with this, the present brief review will focus on B-cell malignancies and how EV can be used as potential biomarkers to follow disease progression and stage. Furthermore, we will explore several proposed strategies aimed at using biologically engineered EV for treatment (e.g., drug delivery mechanisms) as well as for impairing the biogenesis, release, and internalization of cancer-derived EV, with the final objective to disrupt tumor-microenvironment communication.

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…Tumor intrinsic mechanisms generally include genetic aberrations that can affect antigen recognition ('loss/reduction of HLA-I/-II molecules') (16,(115)(116)(117)(118)(119) and influence immune function ('PD-L1/2 upregulation') (120)(121)(122) and immune contexture in TMEs ('oncogenic pathway deregulation') including neoantigen load (83, 84). Tumor cell extrinsic factors that regulate anti-tumor immunity, immune evasion or resistance to immunotherapy involve non-tumor cellular and molecular components within the immune TME including 'upregulation of inhibitory immune checkpoints' (linked to chronic IFN signaling) (123-125), the 'recruitment of TAMs, MDSCs, T Regs' and stromal cells, as well as 'deregulated cytokines and EVs' (126)(127)(128)(129)(130), 'ineffective T cell priming' and 'T cell exclusion' (131)(132)(133)(134)(135).…”

“…Although tumor extrinsic components have been linked to cold or non-inflamed TMEs and response to therapy, it should be noted that their roles in cancer immunology are highly dynamic and context dependent, including the nature and duration of the driving forces implicated. For example, cytokines within immune TMEs including IL-10 ( 131 ), IL-6 ( 132 ) and TGFβ ( 133 ) or extracellular vesicles (EVs) ( 134 , 135 ) are known to have complex, context-dependent effects on both immune and cancer cells. Although there is evidence that these secreted factors have relevant immunomodulatory activity in B cell malignancies including CLL ( 172 – 176 ) and FL ( 177 ), our understanding of the hierarchy and cooperation required between cytokines and chemokines or EVs and their cellular sources for the licensing of immune evasion or the promotion of anti-tumor immune responses is currently ill-defined.…”

“…Tumor B cells induce neoangiogensis and the upregulation of adhesion molecules on ECs ( 243 – 245 , 248 , 252 ). Similarly, lymphoma cells through cell-to-cell contact interactions, secretion of soluble factors and extracellular vesicles (EVs) promote the activation of FRCs and MSCs that contribute to increased tumor survival and neoangiogensis ( 135 , 253 – 255 ). (B) Unlike solid tumors the investigation of the immunosuppressive roles of stroma cells in the lymphoma TME is still in its infancy.…”

“…Moreover, CLL and HL cells secrete EVs that promote the acquisition of a CAF-like phenotype in previously healthy ECs and fibroblasts from different origins ( 267 , 268 ). Importantly, tumor-derived EVs can also modulate other cellular components of the TME ( 269 ), and their role in B-cell malignancies has been recently reviewed ( 135 ).…”

Circulating Exosomal MiR-107 Restrains Tumorigenesis in Diffuse Large B-Cell Lymphoma by Targeting 14-3-3η

“…Besides, miRNA profiles encapsulated into exosomes are prespecified, which refers to the fact that exosomal miRNAs reflect specific information of parental cells. In line with this, accumulating evidence proves exosomal miRNAs as novel biomarkers in early detection, serial monitoring, and prognosis evaluation of hematological malignancies (Drees and Pegtel, 2020;Gargiulo et al, 2020;Seimiya et al, 2020). However, until recently, there are still not abundant studies regarding the predictive role of exosomal miRNAs in DLBCL.…”