IL-2 augments the therapeutic efficacy of adoptively transferred B cells which directly kill tumor cells via the CXCR4/CXCL12 and perforin pathways

Abstract

We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL- 2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemoattraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12- producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor.

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“…Yu et al demonstrated that transforming growth factor β (TGFβ) impairs MSCs ability to secrete CXCL12 and therefore promotes breast cancer metastasis [52], consistent with our findings. Recently, Xia et al found that B cells directly kill BC cells using CXCR4/CXCL12 pathways, indicating that CXCL12 functions as a tumor suppressor [53]. Bioinformatics analysis also suggested that CXCL12 is an independent prognostic indicator.…”

New Insights into Tumor-Infiltrating B Lymphocytes in Breast Cancer: Clinical Impacts and Regulatory Mechanisms

“…The transfer also resulted in the induction of tumor-specific T-cell immunity as measured by cytotoxicity and the productions of cytokine interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor. In similar, TDLN B cells plus IL-2 administration ( 41 ) produced larger amounts of IgG, binding to 4T1, and led to cancer cells lysis. The study also suggested that TDLN B cells could kill cancer cells in CXCR4/CXCL12 pathways by cell-to-cell contact, which termed to be an additive manner.…”

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