Expression of interleukin-4-induced gene-1 (IL4I1) in head and neck squamous cell carcinoma (HNSCC) and its association with macrophage infiltration, tumor staging and efferocytosis

Abstract

Macrophages are antigen-presenting cells that represent a bridge between innate and adaptive immunity. These are phagocytosing cells capable of eliminating apoptotic cells from the microenvironment through an immunologically silent process denominated efferocytosis. Other important characteristic of macrophages is their phenotypical plasticity due to their responsiveness to a variety of external stimuli. Macrophages infiltrate the tumor microenvironment of various solid cancers in large numbers (in HNSCC these cells may account for up to 50% of the tumor mass) and their increased infiltration is generally associated with worse prognosis. Tumor cell-secreted products enhance chemotaxis/migration of peripheral circulation monocytes in an active cell-recruiting process. Once in the tumor microenvironment, external signals will drive their phenotype and biological functions. Given the variability of these external signals (e.g., growth factors, cytokines, hypoxia) in the tumor microenviroment, distinct subpopulations of macrophages arise in different spatial locations in the tumor microenvironment. These macrophage subpopulations differ in their phenotype and biological functions. Recently, expression of interleukin-4-induced gene-1 (IL4I1) by macrophages was identified as a marker of a subpopulation of macrophages with increased efferocytotic activity. Increased expression of IL4I1 is also associated with prognosis in multiple cancer types; however, there is limited information on IL4I1 in HNSCC. In this proposal we will investigate the association between IL4I1 expression in HNSCC and markers of tumor aggressiveness. Using tridimensional spheroid cultures in vitro as a model of tumor microenvironment, we will assess monocyte/macrophage invasion, expression of IL4I1 and phenotype (gene expression) of macrophages.