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.
Highlights
Bevacizumab is a recombinant humanized monoclonalIgG1 antibody that binds to vascular endothelial growth factor and inhibits the proliferation of endothelial cells and the formation of new blood vessels[1]
Acquired resistance to bevacizumab in mouse models accompany with changed cytokines pattern To develop the model of acquired resistance to bevacizumab, breast cancer xenograft bearing mice were treated with bevacizumab until tumor became aggressive, when tumor tissue was transplanted, and tumors were collected at 13 weeks (Fig. 1a)
Compared with time point of 4- week, there is a significant increase in CD31 and VEGF A in 8-week points under bevacizumab treatment (Fig. 1c–d), confirming a resistant phenotype in these tumors
Summary
Bevacizumab is a recombinant humanized monoclonalIgG1 antibody that binds to vascular endothelial growth factor and inhibits the proliferation of endothelial cells and the formation of new blood vessels[1]. Official journal of the Cell Death Differentiation Association. Liu et al Cell Death and Disease (2020)11:993 kinase c-Met[7] in tumor cells and for host cell-mediated resistance, the involvement of tumor-associated macrophages (TAM), myeloid-derived suppressor cells, vascular pericytes and Fibrocyte-like cells[8] mediate acquired resistance to bevacizumab has been reported in mice. The mechanism for bevacizumab resistance has been studied in non-small cell lung cancer[9], glioblastoma[10], and ovarian cancer[11]. The efficacy and mechanisms of bevacizumab on intractable triplenegative breast cancer (TNBC) has not be reported. TAMs are myeloid-derived mononuclear cells with certain phenotypic features, such as CD11b+, CD68+, and F4/80+, and display remarkable plasticity under different micro-environmental stimuli. M2b macrophages (IL10high IL12low CD86+ MHCII+), whose characteristics is between M1 classically activated macrophages with proinflammatory antitumoral function and
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