TY - JOUR
T1 - Tumor-associated neutrophils drive b-cell recruitment and their differentiation to plasma cells
AU - Shaul, Merav E.
AU - Zlotnik, Asaf
AU - Tidhar, Einat
AU - Schwartz, Asaf
AU - Arpinati, Ludovica
AU - Kaisar-Iluz, Naomi
AU - Mahroum, Sojod
AU - Mishalian, Inbal
AU - Fridlender, Zvi G.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85109014733&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-20-0839
DO - 10.1158/2326-6066.CIR-20-0839
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C2 - 33906865
AN - SCOPUS:85109014733
SN - 2326-6066
VL - 9
SP - 811
EP - 824
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 7
ER -