title: Unique Versus Redundant Functions of IL-1α and IL-1β in the Tumor Microenvironment.
abstract: 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.
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, The Faculty of Health Sciences, Ben Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Voronov
authors.forename: Shahar
authors.initials: S
authors.lastname: Dotan
authors.forename: Yakov
authors.initials: Y
authors.lastname: Krelin
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Song
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.forename: Yaron
authors.initials: Y
authors.lastname: Carmi
authors.forename: Peleg
authors.initials: P
authors.lastname: Rider
authors.lastname: Idan Cohen
authors.forename: Marianna
authors.initials: M
authors.lastname: Romzova
authors.forename: Irena
authors.initials: I
authors.lastname: Kaplanov
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
keywords: IL-1; anti-tumor immunity; carcinogenesis; immunogenicity; immunotherapy; tumor invasiveness; tumor-host interactions