B Cell Deficiency Protects Against the Development of c‐MET and Beta‐Catenin Driven Hepatocellular Carcinoma in Mice

ABSTRACT Hepatocellular carcinoma (HCC), a lethal form of liver cancer, continues to show rising mortality rates despite advancements in immunotherapies. This highlights the need for more effective treatments. Recent studies linked the presence of B cells within human tumors, including HCC, to improved responses to immunotherapy and better prognoses. Specifically, tumor‐infiltrating B cells have been associated with reduced cancer cell proliferation, suggesting that B cell‐mediated responses may be harnessed as a potential therapeutic strategy against HCC. However, in advanced HCC, IL‐10‐producing regulatory B cells accumulate and promote tumor growth. These paradoxical findings on B cells in human HCC highlight the necessity for clarifying the specific functions of B cells in HCC development to develop B cell‐targeted therapies. To investigate the role of B cells in HCC, we used B cell‐deficient (muMT) mice and anti‐CD20 antibodies to deplete B cells in WT mice. In both systems, we observed a strong protection against liver tumor formation upon HCC induction, indicating the presence of a potent anti‐tumor effect in the absence of B cells before HCC induction. Additionally, depletion of B cells after tumor foci have formed in the liver at later stage of HCC also potently suppressed tumor growth. Functionally, depletion of CD4 + and CD8 + T cells partially restored susceptibility to tumor growth, suggesting that B cell depletion suppresses HCC development partly through enhanced T cell‐mediated immunity. These findings reveal an underappreciated tumor‐suppressing effect of B cells in HCC and suggest that targeting the mechanisms of B cell suppression may boost anti‐tumor responses in HCC.