Proteomic changes in cerebrospinal fluid from primary central nervous system lymphoma patients are associated with protein ectodomain shedding

Abstract

Primary central nervous system lymphomas (PCNSLs) are mature B-cell lymphomas confined to the central nervous system (CNS). Blood-brain barrier (BBB) dysfunction drastically alters the cerebrospinal fluid (CSF) proteome in PCNSL patients. To reveal the interaction of PCNSL tumors with CNS structures and the vasculature, we conducted a whole-proteome analysis of CSF from PCNSL patients (n = 17 at initial diagnosis) and tumor-free controls (n = 10) using label-free quantitative mass spectrometry. We identified 601 proteins in the CSF proteome using a one-step approach without further prefractionation, and quantified 438 proteins in detail using the Hi-N method. An immunoassay revealed that 70% of the patients in our unselected PCNSL patient cohort had BBB dysfunction. Correlation analysis indicated that 127 (30%) of the quantified proteins were likely increased in PCSNL patients due to BBB dysfunction. After the exclusion of these proteins, 66 were found to differ in abundance (fold-change > 2.0, p < 0.05) between PCNSL and control CSF proteomes, and most of those were associated with the CNS. These data also provide the first evidence that proteomic changes in CSF from PCNSL patients are mainly associated with protein ectodomain shedding, and that shedding of human leukocyte antigen class 2 proteins is a mechanism of tumor-cell immune evasion.