Progressively growing tumors emerge from a unique inflammatory microenvironment derived from the interaction between tumor cells and the host. Tumor angiogenesis is one of the hallmarks of tumor progression and is required for invasiveness and metastasis. Myeloid inflammatory cells, such as immature myeloid precursor cells, also termed myeloid-derived suppressor cells (MDSCs), neutrophils and monocytes/macrophages, are recruited to the tumor microenvironment by factors released by the malignant cells that are subsequently “educated” in situ to acquire a pro-invasive and pro-angiogenic, as well as an immunosuppressive phenotype. The proximity of myeloid cells to endothelial cells (EC) lining blood vessels suggests that they play an important role in the angiogenic response, possibly via secreting a network of cytokines/chemokines and inflammatory mediators. As VEGF is a major angiogenic factor for tumor progression, attempts were made to block the angiogenic response by using anti-VEGF antibodies, or receptor tyrosine kinase inhibitors. Pro-inflammatory mediators were recently shown to play an important role in tumor-mediated angiogenesis and blocking their function can impair tumor progression. Interleukin-1 (IL-1) is an “alarm”, upstream, pro-inflammatory cytokine that is primarily generated by myeloid cells. IL-1 initiates and propagates inflammation, mainly by inducing a local cytokine network and enhancing inflammatory cell infiltration to affected sites and by augmenting adhesion molecule expression on endothelial cells and leukocytes. In this review, we summarize the involvement of IL-1 in tumor-mediated angiogenesis and discuss the future feasibility of IL-1 neutralization approaches in anti-cancer therapy.

Interleukin-1 (IL-1) is a major “alarm” upstream pro-inflammatory cytokine that also affects immunity and hematopoiesis by inducing cytokine cascades. In the tumor arena, IL-1 is produced by malignant or microenvironmental cells. As a pleiotropic cytokine, IL-1 is involved in tumorigenesis and tumor invasiveness but also in the control of anti-tumor immunity. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. In their secreted form, IL-1α and IL-1β bind to the same receptors and induce the same biological functions, but IL-1α and IL-1β differ in their compartmentalization within the producing cell or the microenvironment. IL-1β is only active in its processed, secreted form, and mediates inflammation, which promotes carcinogenesis, tumor invasiveness, and immunosuppression, whereas IL-1α is mainly cell-associated and in the tumor context, when expressed on the cell membrane, it stimulates anti-tumor cell immunity manifested by tumor regression. In the tumor milieu, extracellular levels of IL-1α are usually low and do not stimulate broad inflammation that promotes progression. Immunosuppression induced by IL-1β in the tumor microenvironment, mainly through MDSC induction, usually inhibits or masks anti-tumor cell immunity induced by cell-associated IL-1α. However, in different tumor systems, redundant or unique patterns of IL-1α and IL-1β expression and function have been observed. Recent breakthroughs in inflammasome biology and IL-1β processing/secretion have spurred the development of novel anti-IL-1 agents, which are being used in clinical trials in patients with diverse inflammatory diseases. Better understanding of the integrative role of IL-1α and IL-1β in distinct malignancies will facilitate the application of novel IL-1 modulation approaches at the bedside, in cancer patients with minimal residual disease (MRD), as an adjunct to conventional approaches to reduce the tumor burden.

The role of host-derived IL-1 on the course of Leishmania major infection in susceptible BALB/c mice was assessed. Manifestations of the disease were more severe in mice deficient in the physiological inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra) in comparison with control mice. In mice lacking one of the IL-1 genes (IL-1α or IL-1β), there was delayed development of the disease and more attenuated systemic inflammatory responses. IL-1α-deficient mice were slightly more resistant to L. major infection compared with IL-1β-knockout mice. During disease progression in IL-1Ra KO and control mice, myeloid-derived suppressor cells invaded the spleen, concomitant to suppression of T cell-mediated immunity and expression of systemic high levels of pro-inflammatory cytokines. In IL-1-deficient mice, T_h1 responses were still apparent, even at late stages of the disease. Thus, dose-dependent effects of IL-1 were shown to influence the pathogenesis of murine leishamaniasis in susceptible BALB/c mice. Physiological and supra-physiological levels of IL-1 in the microenvironment promoted an exacerbated form of disease, whereas sub-physiological doses of IL-1 induced a less progressive disease. Thus, manipulation of IL-1 levels in the host, using the IL-1Ra or specific antibodies, has the potential to alleviate symptoms of visceral manifestations of leishmaniasis.

The balance between inflammation and immunity is cardinal for the outcome of the malignant process. Local attenuated inflammatory responses mediated by innate cells may provide accessory signals for the development of acquired immunity against malignant cells. In contrast, excessive inflammatory responses accompany tumorigenesis and tumor invasiveness, by the induction of immunosuppression. In the present study, we have assessed the role of tumor cell-derived IL-1 in determining the invasive versus immunostimulatory potential of tumor cells. For this purpose, we have used 3-MCA-induced fibrosarcoma cell lines from IL-1 knockout (KO) versus control mice. Cell lines with no IL-1 failed to establish tumors in intact mice, while lines obtained from control mice were invasive and induced a potent angiogenic response. In contrast, cell lines from IL-1KO mice were more immunogenic. SDF-1 and IL-6, each induced by IL-1, were the two major cytokines whose levels differed in cell lines with or without IL-1. We could not detect differences in cell surface markers related to immunogenicity, such as MHC Class I, co-stimulatory, or adhesion molecules between both types of cells. However, more T-cells were observed at the inoculation site of tumor cells devoid of IL-1 and more pronounced parameters related to anti-tumor immunity were observed in the spleen (IL-12 and IFNγ) of these mice, compared to mice bearing tumors derived from control mice, where host-derived IL-1 is present. In addition, injection of tumor cells devoid of IL-1, which failed to grow in mice, induced an anti-tumor cell immune memory, while in mice injected with tumor cells from control mice; no immune memory could be detected. From the results, it seems that IL-1 is a crucial factor in determining the balance between immunity and inflammation in tumor-bearing mice. This suggests that manipulation of IL-1 could be useful in anti-tumor therapy, by reducing invasiveness and promoting immunity against the malignant cells.