Exosomes and extracellular vesicles as liquid biopsy biomarkers in diffuse large B‐cell lymphoma: Current state of the art and unmet clinical needs

Abstract

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of non‐Hodgkin's lymphoma, and it constitutes biologically heterogeneous entities. Standard first‐line therapies cure ~60% of patients, the rest being either refractory or experiencing relapse. Currently, there are no robust predictive biomarkers of therapeutic response. Heterogeneity of DLBCL is partly explained by the cell of origin (COO), ie, germinal centre B cell or activated B cell, with the latter exhibiting worse prognosis. While gene expression profiling (GEP) is the gold standard for determining COO, surrogate immunohistochemical algorithms are used clinically, but show significant discordance with GEP. Recently, additional genetic subgroups with different prognoses have been reported. However, the tools/expertise required for analysis prohibit widespread deployment. Liquid biopsy‐based assays show promise in providing clinically actionable information, are noninvasive and facilitate serial sampling to assess mechanisms of therapy resistance. Circulating, cell‐free DNA analysis has shown enhanced sensitivity for detecting molecular alterations, but this modality cannot determine alterations of the tumor proteome or on signalling pathways. Exosomes are endosomally derived vesicles, are found in high abundance in body fluids and are readily isolated using a variety of methods. Tumour‐derived exosomes can yield data regarding genetic, transcriptional, and proteomic changes useful for diagnosis, prognosis, and therapy of DLBCL. At present, standardized techniques for isolating exosomes are lacking and discriminating between exosomes from neoplastic and normal B cells is challenging. Refinements in isolation procedures are required to realize their full potential as precision medicine tools to provide comprehensive information on disease subtypes, identify prognostic factors, allow real‐time monitoring of therapy response and delineate novel drug targets.

Proteomic Landscape of Extracellular Vesicles for Diffuse Large B-Cell Lymphoma Subtyping

“…EVs carry molecular traits of the parental cells and therefore are a potential source of biomarker molecules for diagnosis and prognosis of DLBCL [13]. EVs have been explored as liquid biopsy biomarkers in DLBCL particularly targeting nucleic acids such as circulating RNA, noncoding RNA, and miRNA [31][32][33]. Concerning EV proteins, previous studies used predefined wellstudied lymphoma-related biomarkers [34,35].…”

Human Serum Extracellular Vesicle Proteomic Profile Depends on the Enrichment Method Employed

“…For that reason, EVs analysis has become a key element for liquid biopsy protocols applicable to clinical routine [ 12 , 13 ], with the publication of guidelines to try to unify criteria for the researcher in this field [ 14 ]. Regarding proteomic analysis, several studies have recently been conducted to optimize the conditions to obtain high purity EVs [ 15 ] or compare different methods for EV purification [ 16 ].…”

Clinical Application of Liquid Biopsy in Non-Hodgkin Lymphoma

“…Exosomes are a type of endosome-derived extracellular vesicle with a diameter ranging from 30 to 120 nm ( 2 ). Exosomes typically contain nucleic acids, proteins, lipids, and metabolites ( 26 ).…”

“…This heterogeneity is reflected by significant differences in the responses of these tumors to the standard first-line treatment strategy, known as R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, and prednisone). Approximately 20%–50% of patients experience relapse or develop drug-resistance after treatment ( 2 ). The 5-year survival rates for DLBCL reported for the United States and Europe are 63.8% and 55.4%, respectively ( 2 ).…”

“…Approximately 20%–50% of patients experience relapse or develop drug-resistance after treatment ( 2 ). The 5-year survival rates for DLBCL reported for the United States and Europe are 63.8% and 55.4%, respectively ( 2 ). Primary central nervous system lymphoma (PCNSL) is a rare type of primary extranodal NHL that originates in the brain parenchyma, cranial nerves, leptomeninges, eyes, or spinal cord, without affecting other sites.…”