Cross-talk between Myeloid and B Cells Shapes the Distinct Microenvironments of Primary and Secondary Liver Cancer

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG(+) plasma cells preferentially accumulated in HCC, whereas IgA(+) plasma cells were preferentially enriched in CRLM. Mechanistically, IgG(+) plasma cells in HCC were recruited by tumor- associated macrophages via the CXCR3-CXCL10 axis, whereas IgA(+) plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG(+) plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA(+) plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG(+) plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA(+) plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell- mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.