Regulatory B Cells: Key Players in Hepatocellular Carcinoma Progression

Abstract

Hepatocellular carcinoma (HCC) represents a major health problem and ranked as the sixth most common cancer worldwide and the third most common cause of cancerrelated mortality. The prognosis of HCC is usually poor due to post surgery recurrence and metastasis. Both Cells mediated and humoral immunity is considered as key players in the immunopathology of HCC. Recently, there is a special subset of B cells defined as regulatory B cells (Bregs) found to be abundant in the tumor microenvironment and was a leading cause of progression of various cancers, including HCC.Bregs arise from a common progenitor named transitional 2 marginal zone precursor (T2-MZP) B cells as they have most of the indicated markers for Bregs. Human Bregs or also known as human IL-10 producing B cells (B10) is a subset of B cells is enriched in the CD19 + CD24 high CD27 − CD38 high CD1d high CD5 + transitional B cell subset. Tumor-Evoked Regulatory B Cells (tBreg) exert antitumor activity by promoting conversion of the resting CD4 + T cell into FoxP3 + Treg by secretion of TGF-β then the Treg inhibit T cell proliferation and promote tumor metastasis by suppression of the anti-tumor effects of CD8 + T cells and NK cells.Bregs may suppress the antitumor immunity and promote HCC progression via several mechanisms including the CD40/CD40L signaling-mediated cytokine production of IL10, TGF-β which down regulate TNF-α, PD-1 hi B-cell, Granzyme B secreting B cells (GrB+ B cells), Treg upregulation, TH17 downregulation and IL35 which triggers the genesis of Tregs from naive T cells with subsequent suppression of the anticancer immune response. The hallmark of Breg function is IL-10, which inhibits proinflammatory cytokines and supports Treg differentiation. In this review, we highlight the role and mechanisms by which Breg cells are involved in HCC. Understanding these mechanisms may direct us to a novel therapeutic approach targeting Breg for treatment of HCC.

Reversion of tumor hepatocytes to normal hepatocytes during liver tumor regression in an oncogene-expressing transgenic zebrafish model

“…BCR signaling activates multiple signaling cascades involving kinases, GTPases and transcription factors, and contributes to survival and proliferation. While activation of B cells in the tumor microenvironment is known to promote the progression of various cancers, including HCC (Hetta et al, 2016), it is possible that the continuously activated immune pathways contributed to the survival of tumor hepatocytes during tumor regression. Ingenuity canonical pathway analysis revealed that the Gα12/13 and NGF signaling, which were upregulated in tumor hepatocytes, retained their activation state in tumor-reverted hepatocytes but not in the newly differentiated hepatocytes.…”

Frequency and Implications of myeloid‐derived suppressor cells and lymphocyte subsets in Egyptian patients with hepatitis C virus‐related hepatocellular carcinoma

“…HCC is considered one of the most common malignancies and major health problems worldwide . In Egypt, HCC is the second most common cancer in men and the sixth most common cancer in women . Hospital‐based studies from Egypt have reported an overall increase in the relative frequencies of all liver‐related cancers in Egypt, from approximately 4% in 1993 to 7.3% in 2003 …”

Circulating hematopoietic stem cells, endothelial progenitor cells and cancer stem cells in hepatocellular carcinoma patients: contribution to diagnosis and prognosis

“…Despite advances in curative treatment modalities for HCC including surgical resection, liver transplantation and radiofrequency ablation [5][6][7][8], high recurrence rates still limit overall patients' survival [9]. Therefore, understanding the fundamental biological changes in HCC responsible for its rapid growth and metastasis is essential to guide the development of new therapeutic options [10][11][12].…”