The Role of IL-1β in the Early Tumor Cell–Induced Angiogenic Response

Abstract

In this study, we assessed the involvement of IL-1β in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1β and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1β and VEGF circuit acts through interactions between bone marrow–derived VEGF receptor 1+/IL-1R1+ immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1β and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1β or recombinant VEGF. We have shown that IL-1β inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1+/IL-1R1+ cells to express hypoxia inducible factor-1α, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1β inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic.

IL-1 Receptor Antagonist Chimeric Protein: Context-Specific and Inflammation-Restricted Activation

“…Surrounded by myeloid cells, such as neutrophils and macrophages, these foci are plentiful with enzymes and cytokines, including NK cell-derived granzymes. Indeed, IL-1R blockade was shown to be effective in reducing tumor size, angiogenesis, and metastases in several setups (9,35,36), and there is now documented benefit of blocking IL-1 in patients with cancer (37). However, cancer patients are often treated for prolonged periods with bone-marrow suppressing drugs and, therefore, are exposed to an increased risk of infection.…”

Blocking IL1β Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis

“…IL1b plays a major role in tumor angiogenesis, which represents one of the main mechanisms of facilitating tumor invasiveness, and its blockade by IL1Ra was shown to reduce the tumor angiogenic response (17,18). We therefore further characterized the effect of anakinra as a single agent or in combination with paclitaxel chemotherapy on the tumor's vasculature.…”

Inflammation and skeletal metastasis

“…86 Furthermore, in a melanoma model, myeloid cell-derived IL-1b induced paracrine VEGF expression in endothelial cells and the activation of an amplification loop that promoted angiogenesis, inflammation and tumor progression. 87 In addition to their role in metastasis and chemoresistance, myeloid cells (CD11b þ /Gr1 þ ) suppress the antitumor response mediated by CD8 þ T cells. 88 In this model of pancreatic carcinoma, tumor cells produced GM-CSF driving the recruitment and development of suppressive CD11b þ /Gr1 þ cells.…”