A major mechanism through which neutrophils have been suggested to modulate tumor progression involves the interaction and subsequent modulation of other infiltrating immune cells. B cells have been found to infiltrate various cancer types and play a role in tumor immunity, offering new immunotherapy opportunities. Nevertheless, the specific impact of tumor-associated neutrophils (TAN) on B cells has largely been overlooked. In the current study, we aimed to characterize the role of TANs in the recruitment and modulation of B cells in the tumor microenvironment (TME). We showed that TANs actively participate in the recruitment of B cells to the TME and identified TNFα as the major cytokine mediating B-cell chemotaxis by TANs. The recruitment of CD45+B220+CD138− splenic B cells by TANs in vitro resulted in B-cell phenotypic modulation, with 68.6% ± 2.1% of the total migrated B cells displaying a CD45−B220+CD138+ phenotype, which is typical for plasma cells. This phenotype mirrored the large proportion (54.0% ± 6.1%) of CD45−B220+CD138+ intratumoral B cells (i.e., plasma cells) in Lewis lung carcinoma tumors. We next confirmed that the differentiation of CD45+B220+CD138− B cells to functionally active CD45−B220+CD138+ plasma cells required contact with TANs, was independent of T cells, and resulted in IgG production. We further identified membranal B-cell activating factor (BAFF) on TANs as a potential contact mechanism mediating B-cell differentiation, as blocking BAFF-receptor (BAFF-R) significantly reduced IgG production by 20%. Our study, therefore, demonstrates that TANs drive the recruitment and modulation of B cells into plasma cells in the TME, hence opening new avenues in the targeting of the immune system in cancer.
F. nucleatum is an anaerobic bacterium that is associated with several tumor entities and promotes tumorigenesis. Recent evidence suggests that F. nucleatum binds the inhibitory receptor carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) via the trimeric autotransporter adhesin CbpF. However, whether this binding is functional or whether other fusobacterial trimeric autotransporter adhesins are involved in CEACAM1 activation is unknown. In this study, using F. nucleatum mutants lacking the type 5c trimeric autotransporter adhesins fvcA (CbpF), fvcB, fvcC, and fvcD, we show that F. nucleatum CbpF binds and activates CEACAM1 and also binds carcinoembryonic antigen (CEA), a tumor-associated protein. We further find that CEACAM antibodies directed against the CEACAM N-terminal domain block the CbpF-CEACAM1 interaction. In functional assays, we demonstrate CbpF-dependent inhibition of CD4+ T cell response. Thus, we characterize an immune evasion mechanism in which F. nucleatum uses its surface protein CbpF to inhibit T cell function by activating CEACAM1.
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