Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

Abstract

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

Keywords: IL-1; cancer; resistance.

Figure 1

Schematic representation of the role of IL-1 in tumor progression. The upper panel represents two sources of IL-1. Specifically, the tumor-derived IL-1 (upper left) establishes an auto-stimulatory loop that sustains IL-1 synthesis and release, while the tumor microenvironment-derived IL-1 (upper right) arises from immune cells of the myeloid origin: myeloid-derived suppressor cells (MDSC), macrophage-polarized M2 phenotype, regulatory B (Breg) and T helper (Th17) cells. As shown in the figure, the boost of IL-1, released from both tumor and immune cells, induces a wide range of effects: it sustains the production of Reactive Oxygen Species (ROS), and Nitric Oxide (NO) that exacerbate mutation rate rescuing cells from apoptosis; it increases the production of chemokines, cytokines and all adhesion molecules responsible for vascular permeability, leading to angiogenesis and metastasis. It recruits immunosuppressive cells (MDSC, M2 macrophages, neutrophils and Th17) and activates stromal cells in the TME [88,89,90,91]. Finally, IL-1 is described to be involved in drug resistance through the induction of anti-apoptotic signals and senescence.