The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment

Abstract

The high metabolic needs of T lymphocytes in response to activation make them particularly vulnerable to modifications of their biochemical milieu. Immunosuppressive enzymes produced in the tumor microenvironment modify nutrient availability by catabolizing essential or semi-essential amino acids and producing toxic catabolites, thus participating in the local sabotage of the antitumor immune response. L-amino-acid oxidases are FAD-bound enzymes found throughout evolution, from bacteria to mammals, and are often endowed with anti-infectious properties. IL4I1 is a secreted L-phenylalanine oxidase mainly produced by inflammatory antigen-presenting cells—in particular, macrophages present in T helper type 1 granulomas and in various types of tumors. In the last decade, it has been shown that IL4I1 is involved in the fine control of B- and T-cell adaptive immune responses. Preclinical models have revealed its role in cancer immune evasion. Recent clinical data highlight IL4I1 as a new potential prognostic marker in human melanoma. As a secreted enzyme, IL4I1 may represent an easily targetable molecule for cancer immunotherapy.

RNA Sequencing of H3N2 Influenza Virus-Infected Human Nasal Epithelial Cells from Multiple Subjects Reveals Molecular Pathways Associated with Tissue Injury and Complications

“…Finally, RNAseq also unraveled expression changes of certain newly-discovered genes in response to influenza infection of the upper airway cells. Genes such as HEATR9 [23], IL4I1 [24], TNFSF13B ( BAFF ) [25], and PDCD1 ( PD-1 ) [26] are recently implicated in influenza pathogenesis and mucosal defense, thereby signifying the role of the nasal epithelium against influenza infection. Furthermore, RNAseq identified altered expression of ART3 and KCNH7 genes that were not previously detected in influenza transcriptomes.…”

Rapid host response to an infection with Coronavirus. Study of transcriptional responses with Porcine Epidemic Diarrhea Virus

“…The gene coding for the amine oxidase “Interleukin 4 Induced 1” (IL4I1) was strongly down-regulated (30-fold) 4h after infection with PEDV. Besides catalysis of L-Phenylaniline into Phenylpyruvate (Fig.3), IL4I1 also fulfills an important role in signaling in “synaptic clefts” formed between antigen presenting cells (APC) and T cells (so-called “immune cleft”: see also below)(30: Boulland et al 2007, 31: Molinier-Frenkel et al 2019).…”

“…data provided in the GeneCards reports of these genes/proteins. The drawing was inspired by figures presented in the publications of Molinier-Frenkel et al (31:2019) and Sattentau (32: 2008).…”

“…IL4I1 is believed to be secreted from APC’s (e.g. DC’s) in the immune cleft formed with T cells (31: Molinier-Frenkel et al 2019). The mechanism how IL4I1 transmits its signal to T cells is not completely understood.…”

IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

“…It is mainly produced by macrophages and dendritic cells (DCs) in the context of pro-T helper type 1 (Th1) inflammatory stimuli (3). IL4I1 is particularly abundant in the tumor microenvironment of inflammatory human cancers and may be associated with a poor prognosis [reviewed in (4)]. Indeed, murine models have shown that IL4I1 negatively regulates the expansion and functionality of antitumor CD8 + T cells (5,6), an effect that has been confirmed by the analysis of human primary cutaneous melanomas (7).…”