Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion

Abstract

BackgroundRegulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown.MethodsFlow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1+Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test. TIM-1+Breg cells and CD8+ T cells were isolated, stimulated and/or cultured in vitro for functional assays. Exosomes and B cells were isolated and cultured in vitro for TIM-1+Breg cell expansion assays.ResultsPatients with HCC showed a significantly higher TIM-1+Breg cell infiltration in their tumor tissue compared with the paired peritumoral tissue. The infiltrating TIM-1+Breg cells showed a CD5highCD24−CD27−/+CD38+/high phenotype, expressed high levels of the immunosuppressive cytokine IL-10 and exhibited strong suppressive activity against CD8+ T cells. B cells activated by tumor-derived exosomes strongly expressed TIM-1 protein and were equipped with suppressive activity against CD8+ T cells similar to TIM-1+Breg cells isolated from HCC tumor tissue. Moreover, the accumulation of TIM-1+Breg cells in tumors was associated with advanced disease stage, predicted early recurrence in HCC and reduced HCC patient survival. Exosome-derived HMGB1 activated B cells and promoted TIM-1+Breg cell expansion via the Toll like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways.ConclusionsOur results illuminate a novel mechanism of TIM-1+Breg cell-mediated immune escape in HCC and provide functional evidence for the use of these novel exosomal HMGB1-TLR2/4-MAPK pathways to prevent and to treat this immune tolerance feature of HCC.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0451-6) contains supplementary material, which is available to authorized users.

Roles of circRNAs in the tumour microenvironment

“…3CircRNAs act as protein/ peptide translators. CircRNAs are reported to function as translation templates, and they may encode proteins/ peptides involved in tumour pathogenesis and progress [57,58]. 4CircRNAs act as regulators of gene transcription and expression.…”

“…1b). Studies have shown that tumour cell-derived exosomes are involved in multiple immune activities in tumour progression [58,70,71]. In addition, some exosomal RNAs from donor cells, including circRNA, can function in recipient cells [72][73][74].…”

Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma—An Overview

“…TIM-1 + Breg cells create a microenvironment in which IL-10 is secreted and the activity of CD8+ T is impaired, thus favoring HCC progression. These data could be the basis for the development of immunotherapy strategies in HCC [55].…”

Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy

“…Few studies have shown that TEXs induce differentiation of naïve B cell to a regulatory phenotype with production of inhibitory cytokines that leads to antitumor immune response inhibition. 147,148 In addition, TEXs could reduce antibody-dependent cell cytotoxicity (ADCC) through interfering with tumor-reactive antibodies binding to tumor cells. 149 In contrast, TEXs were also described to drive antibody production, the underlying mechanism remaining to be explored.…”