Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

Abstract

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of the disease with lack of recognized molecular targets for therapy. TNBC cells are known to secrete high levels of the proinflammatory cytokines interleukin‐6 (IL‐6) and IL‐8, which promote angiogenesis and favor the growth and spread of the disease. In the present study, we have shown that the humanized anti‐IL‐6 receptor tocilizumab (Actemra) is also a potent inhibitor of IL‐8 in TNBC cells. Similar effect was also obtained by specific IL‐6 inhibition either by small interfering RNA or by neutralizing antibody. Likewise, neutralizing IL‐8 with specific antibody downregulated IL‐8 and inhibited the IL‐6/signal transducer and activator of transcription 3 and nuclear factor‐κB pathways. Interestingly, simultaneous co‐inhibition of IL‐6 and IL‐8 did not increase the effects of the single inhibitors. Additionally, we present clear evidence that tocilizumab has potent antiangiogenic effect. Indeed, tocilizumab abolished the ability of TNBC cells to induce the differentiation of endothelial cells into network‐like tubular structures in vitro and impaired neovascularization in humanized breast orthotopic tumor xenografts. This was associated with tocilizumab‐dependent downregulation of the main proangiogenic factor vascular endothelial growth factor A and its coactivator hypoxia‐inducible factor 1 both in vitro and in vivo. Therefore, tocilizumab could be of great therapeutic value for TNBC patients through targeting angiogenesis.

STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

“…Similar results have also been observed in non-small-cell lung cancer cells [ 128 ]. IL-6 antibody treatment inhibits in vitro cell proliferation and in vivo tumor growth in both ER+ MCF7 cells and TNBC, MDA-MB-231 cells through a blockade of STAT3 activation and associated downregulation of STAT3 target genes including SOCS3, IL6ST and genes involved in angiogenesis [ 129 , 130 ]. Treatment with Tocilizumab in mouse models of hormone-therapy-resistant breast cancer can also re-sensitize tumors to Tamoxifen treatment, highlighting the importance of the IL-6-IL-6R-ER axis in hormone receptor positive disease [ 94 ].…”

Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against Prostate Cancer Cells

“…For example, it has been reported that inhibition of the IL-6-JAK/STAT-3 signaling pathway in CRPC cells (C4-2 and CWR22Rv1) sensitizes tumor cells to NK cell-mediated cytotoxic action through changes in the PDL-1 ligand interaction and the expression of NKG2D [ 56 ]. Additionally, tocilizumab has already been used in some cancer models with important effects in different tumor cell models, mainly on the proliferation, invasion, and sensitization to drugs through dephosphorylation of STAT-3 [ 29 , 57 – 59 ]. Recently, tocilizumab has been proposed as a component of combination therapy with other targeted monoclonal antibodies against immune checkpoints in phase I/II studies against multiple myeloma ( NCT04910568 ) and melanoma ( NCT03999749 ); interestingly, there is no such combined therapy targeted directly to prostate cancer as of yet.…”

Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

“…In our study, we found after co-culture with Treg, only tumor cell U251 produced IL6, which suggested that tocilizumab may directly act on tumor cells, not on Tregs. However, it also has been reported that tocilizumab could inhibit tumor growth through impairing tumor-related neovascularization and main proangiogenic factor VEGF-A and its transactivator HIF-1α in humanized breast orthotopic tumor xenografts [ 51 ]. Yujia Zheng also reported that tocilizumab prevented CD39 expression on NK cells induced by IL6 derived by esophageal squamous cell carcinoma cells, which suggested that tocilizumab may inhibit tumor growth via affecting NK cells [ 52 ].…”