Margin-Infiltrating CD20+ B Cells Display an Atypical Memory Phenotype and Correlate with Favorable Prognosis in Hepatocellular Carcinoma

Abstract

Purpose: The role of infiltrating B cells in hepatocellular carcinoma has been overlooked for many years. This study is aimed to delineate the distribution, prognostic value, and functional status of B cells in human hepatocellular carcinoma.Experimental design: Immunohistochemistry was used to investigate the distribution and clinical significance of infiltrating CD20þ B cells in a series of 120 patients with hepatocellular carcinoma. The results were further tested in an independent series of 200 patients with hepatocellular carcinoma. The functional status of CD20 þ B cells was determined by flow cytometry, immunofluorescence, and in vitro coculture assay.Results: Infiltrating CD20 þ B cells were predominantly concentrated in the tumor invasive margin, compared with the peri-and intratumor areas. High density of margin-infiltrating B lymphocytes (MIL-B) positively correlated with small tumor size, absence of vascular invasion, and increased density of CD8 þ T cells (P < 0.05). Survival analyses revealed that increased number of MIL-Bs and their penetration through the tumor capsule were significantly associated with improved overall and recurrence-free survival, and were identified as independent prognosticators for patients with hepatocellular carcinoma (P < 0.05). Importantly, the results were further validated in another independent hepatocellular carcinoma cohort. Moreover, we found that MIL-Bs featured an atypical memory phenotype (IgDexpressed surface markers characteristic of antigen-presenting cells, possessed tumor-killing potential by producing IFN-g, interleukin 12p40 (IL-12p40), granzyme B, and TRAIL, and acted in cooperation with CD8 þ T cells. Conclusions:The profile of CD20 þ B cells in situ is a new predictor of prognosis for patients with hepatocellular carcinoma and provides a novel target for an optimal immunotherapy against this fatal malignancy.

TIM-4 Identifies IFN-γ–Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection

“…We also noted that a portion of transferred TIM-4 + B cells infiltrate the tumor, suggesting that Be1 cells may exert at least part of their effector function locally. Of note, tumor infiltration with B cells and B cell: CD8 + T cell interactions within ovarian and various other cancers are associated with improved prognosis (19, 52, 53). Interestingly, we did find occasional TIM-4 + B cells that were closely associated with CD8 + TILs (Supplemental Fig.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…In accordance with these last functions, Nielsen et al observed in ovarian cancer that tumor-infiltrating CD20 + B cells were often found in close proximity to CD8 + T cells, expressed MHC Class I, MHC Class II, CD80, and CD86 molecules, and that the presence of combined CD20 + and CD8 + lymphocytes was associated with prolonged patient's survival . The expression of surface markers' characteristic of APC by tumor-infiltrating B cells was also described in primary lung cancer (Yasuda et al, 2002) and in hepatocellular carcinoma (Shi et al, 2013). Finally, few studies suggested that some tumorinfiltrating B cells could act as true killer cells, through the expression of granzyme B and TRAIL (Shi et al, 2013), or in a Fas Ligand-dependent manner (Tao et al, 2015).…”

“…The expression of surface markers' characteristic of APC by tumor-infiltrating B cells was also described in primary lung cancer (Yasuda et al, 2002) and in hepatocellular carcinoma (Shi et al, 2013). Finally, few studies suggested that some tumorinfiltrating B cells could act as true killer cells, through the expression of granzyme B and TRAIL (Shi et al, 2013), or in a Fas Ligand-dependent manner (Tao et al, 2015).…”

Tertiary Lymphoid Structures: An Anti-tumor School for Adaptive Immune Cells and an Antibody Factory to Fight Cancer?

“…B lymphocytes could also influence T cell polarization and functions by secreting type 1 (IL-12, IFN-γ), type 2 (IL-4, IL-13), and immune suppressive (IL-10, IL-35, TGF-β) cytokines. Production of IL-12 and IFN-γ by intra-tumoral B lymphocytes in hepatocellular carcinoma indicates a putative role of these cells in the induction and/or the amplification of a strong cellular immune response (30). However, tumor-infiltrating B cells could also act as negative regulators of the anti-tumor response, as already discussed for the role of IgA produced locally (see above).…”