Abstract
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 TNFa as the major cytokine mediating B-cell chemotaxis by TANs. The recruitment of CD45 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 phenotype, which is typical for plasma cells. This phenotype mirrored the large proportion (54.0% ± 6.1%) of CD45-B220 intratumoral B cells (i.e., plasma cells) in Lewis lung carcinoma tumors. We next confirmed that the differentiation of CD45 B cells to functionally active CD45-B220 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.
| Original language | American English |
|---|---|
| Pages (from-to) | 811-824 |
| Number of pages | 14 |
| Journal | Cancer Immunology Research |
| Volume | 9 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2021 |
Bibliographical note
Funding Information:M.E. Shaul reports grants from Israel Science Foundation, Sasson and Luisa Naor Fund, The Cooperation Program in Cancer Research of the Deutsches Krebs-forschungszentrum (DKFZ) and Israel's Ministry of Science and Technology (MOST), and Joint Research Fund of the Hebrew University and Hadassah Medical Center during the conduct of the study, as well as a patent for ID-6494–1 pending and licensed to Immunyx. A. Zlotnik reports grants from Israel Science Foundation and Sasson and Luisa Naor Fund during the conduct of the study. L. Arpinati reports grants from Israel Science Foundation, Sasson and Luisa Naor Fund, and German Cancer Research Center DKFZ during the conduct of the study. N. Kaisar-Iluz reports grants from Israel Science Foundation and Sasson and Luisa Naor Fund during the conduct of the study. S. Mahroum reports grants from Israel Science Foundation and Sasson and Luisa Naor Fund during the conduct of the study. I. Mishalian reports grants from Israel Science Foundation and Joint Research Fund of the Hebrew University and Hadassah Medical Center during the conduct of the study. Z.G. Fridlender reports grants from Israel Science Foundation, Sasson and Luisa Naor Fund, The Cooperation Program in Cancer Research of the Deutsches
Funding Information:
This work was supported by a grant from the Israel Science Foundation, the Sasson and Luisa Naor Fund, The Cooperation Program in Cancer Research of the DKFZ and Israel's Ministry of Science and Technology (MOST), and a grant from the Joint Research Fund of the Hebrew University and Hadassah Medical Center.
Publisher Copyright:
© 2021 American Association for Cancer Research.
