Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma.
OBJECTIVE
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.


METHODS
Immunohistochemistry was used to investigate the distribution and clinical significance of infiltrating CD20(+) 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(+) B cells was determined by flow cytometry, immunofluorescence, and in vitro coculture assay.


RESULTS
Infiltrating CD20(+) 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(+) 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 (IgD(-)IgG(+)CD27(-)CD38(-)), expressed surface markers characteristic of antigen-presenting cells, possessed tumor-killing potential by producing IFN-γ, interleukin 12p40 (IL-12p40), granzyme B, and TRAIL, and acted in cooperation with CD8(+) T cells.


CONCLUSIONS
The profile of CD20(+) 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.
Authors' Affiliations: Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, and Institute of Biomedical Sciences, Fudan University, Shanghai, PR China.
Jie-Yi
JY
Shi
Qiang
Q
Gao
Zhi-Chao
ZC
Wang
Jian
J
Zhou
Xiao-Ying
XY
Wang
Zhi-Hui
ZH
Min
Ying-Hong
YH
Shi
Guo-Ming
GM
Shi
Zhen-Bin
ZB
Ding
Ai-Wu
AW
Ke
Zhi
Z
Dai
Shuang-Jian
SJ
Qiu
Kang
K
Song
Jia
J
Fan
D000328:Adult; D000368:Aged; D018951:Antigens, CD20 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D008113:Liver Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D047368:Tumor Burden
D018951:Antigens, CD20