Tumor-Associated Neutrophils Drive B-cell Recruitment and Their Differentiation to Plasma Cells

• Published in: Cancer immunology research 2021-07, Vol.9 (7), p.811-824
• Main Authors: Shaul, Merav E, Zlotnik, Asaf, Tidhar, Einat, Schwartz, Asaf, Arpinati, Ludovica, Kaisar-Iluz, Naomi, Mahroum, Sojod, Mishalian, Inbal, Fridlender, Zvi G
• Format: Article
• Language: English
• Subjects: Animals; B-Cell Activating Factor - metabolism; B-Cell Activation Factor Receptor - antagonists & inhibitors; B-Cell Activation Factor Receptor - metabolism; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Cell Differentiation - immunology; Cell Line, Tumor; Chemotaxis, Leukocyte - immunology; Disease Models, Animal; Female; Humans; Lymphocyte Activation; Mice; Neutrophils - immunology; Neutrophils - metabolism; Plasma Cells - immunology; Plasma Cells - metabolism; Tumor Microenvironment - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-20-0839

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 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.