Tumor necrosis factor α inhibition overcomes immunosuppressive M2b macrophage-induced bevacizumab resistance in triple-negative breast cancer

Abstract

Bevacizumab in neoadjuvant therapy provides a new hope of improved survival for patients with triple-negative breast cancer (TNBC) by targeting vascular endothelial growth factor in combination with chemotherapy, but curative effect is limited by bevacizumab’s continuous use while mechanisms remain incompletely understood. More and more researches reported that tumor-associated macrophages mediate resistance to chemotherapy and radiotherapy in various tumors. Here we developed a TNBC model resistant to bevacizumab under bevacizumab continuous administration. It was found that proportion of a specific subset of tumor-associated macrophages characterized as M2b (CD11b+ CD86high IL10high) increased and responsible for acquired resistance to bevacizumab. Then, we showed that RAW264.7 macrophages could be polarized to M2b subtype on simultaneous exposure to bevacizumab and TLR4 ligands as occurs in the context of continuous bevacizumab treatment. Concordantly, in TLR4-deleted C57BL/10ScNJNju (TLR4lps–del) mut/mut mice with bevacizumab treatment model, it was verified that the M2b macrophage could be induced by Fc gamma receptor-TLR4 cross-talk. In MDA-MB-231-resistant tumor-bearing mice, the content of TNFα in serum kept going up consistent with CCL1, a chemokine of M2b macrophage. In vitro neutralizing tumor necrosis factor α (TNFα) could inhibit the tumor progression caused by M2b culture medium and tumor IDO1 expression. Therefore, we thought that TNFα is a key tumor-promoting effector molecule secreted by M2b macrophage. Accordingly, the curative effect of bevacizumab was proved to be significantly improved by neutralizing TNFα with anti-TNFα nanobody. This study is expected to provide theoretical and clinical evidence elucidating the drug resistance in patients receiving bevacizumab.

TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

“…TNFα also facilitates the installment of an effector T cell hostile milieu via indoleamine 2,3-dioxygenase 1 (IDO1) accumulation in the TME. To illustrate, while M2b polarized macrophage conditioned medium stimulates tumor cell proliferation and IDO1 expression in vitro, this is reduced upon TNFα neutralization [88]. As IDO1 converts tryptophan into kynurenine, tryptophan is deprived with subsequent installment of TAA-specific T cell anergy, while Treg activity, lymphangiogenesis, and neovascularization are enhanced in vivo.…”

Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain

“…Real-time PCR analysis revealed that RAW264.7 macrophages treated with CpG-ODNs and an anti-PD-1 antibody exhibited a statistically significant increase in the mRNA expression of cytokines (TNF-α, IL-6), chemokines (CCL1 and CCL2) and activation markers (CD80 and CD86), which suggests the acquisition of the M2b phenotype, an immunoreg-ulatory phenotype [44]. This particular M2 macrophage subtype, which was reported to be generated by the concomitant activation of TLRs and Fc receptors and involved in immunosuppression, cancer progression and resistance to therapy [53,54], expresses various genes [44], specifically those with expression levels that were upregulated by the combination of CpG-ODNs and the anti-PD-1 antibody in our cellular model. Accordingly, the expression of chemokine CCL1, which is considered a specific marker of M2b macrophages [44], was markedly increased in the combinatorial treatment group compared to single-agent-treated groups.…”

Resibufogenin Suppresses Triple-Negative Breast Cancer Angiogenesis by Blocking VEGFR2-Mediated Signaling Pathway

“…Therefore, targeting tumor blood vessels has been considered as a reasonable approach to the treatment of various malignancies (Rajabi and Mousa, 2017). Bevacizumab, a recombinant humanized monoclonal IgG1 antibody that binds to VEGF, provides a new hope of improved survival for patients with intractable TNBC in combination with paclitaxel and capecitabine (Liu et al, 2020). However, this neoadjuvant therapy cannot fully meet the expectations of patients for higher overall survival owing to acquired resistance.…”

“…Therefore, inhibiting tumor angiogenesis keeps an attractive strategy for oncotherapy since decades ago. To date, bevacizumab is the only antiangiogenic drug approved by FDA (Food and Drug Administration) for TNBC (Xie et al, 2021), whereas bevacizumab has little effect on overall survival due to acquired drug resistance (Liu et al, 2020) and its limitation of blocking VEGFA expression (Zou et al, 2020). It is essential to find antiangiogenic medicines with novel skeleton for antiangiogenesis therapy and to overcome drug resistance.…”