A team of researchers at the German Cancer Research Center (DKFZ) and the Berlin Institute of Health (BIH) have released new data that highlights a potential new target for cancer immunotherapies. The scientists found that the metabolic enzyme IL4I1 (Interleukin-4-Induced-1) promoted the spread of tumor cells and suppressed the immune system. This enzyme, which activates the dioxin receptor, is produced in large quantities by tumor cells. Findings from the new study, published recently in Cell through an article entitled “IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression,” suggest that substances which inhibit IL4I1 could open up new opportunities for cancer therapy.
Immunotherapies activate the body’s own defense against tumors and are currently revolutionizing cancer therapy. Despite some groundbreaking successes, however, only a small number of patients benefit from the drugs currently available. The researchers investigated the molecular mechanisms by which tumors escape destruction by the immune system. Their research results may provide important information for the development of new immunotherapy concepts.
The aryl hydrocarbon receptor (AHR) is also known as the dioxin receptor because it mediates the toxic effect of dioxins. However, not only toxins but also the body’s metabolic products can activate the receptor. An example of this is degradation products of the amino acid tryptophan, which we take in with our food as a building block of proteins. Tumors use these metabolites to their advantage: They promote the mobility of cancer cells and weaken the immune response against tumors.
One molecule, in particular, caught the scientists’ eye: the enzyme IL4I1. No other enzyme of the tryptophan metabolism was as strongly linked to an activation of the dioxin receptor as IL4I1: “The metabolites formed by IL4I1 bind to the dioxin receptor and activate it, which leads to the suppression of immune cells,” explained study co-author Saskia Trump, PhD, deputy head of the Research Group in Molecular Epidemiology at BIH.
“AHR activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity,” the authors wrote. “The context specificity of AHR target genes has so far impeded the systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice.”
Of clinical interest is the observation that the survival probability of patients with gliomas, a type of malignant brain tumor, decreased when the enzyme was present in higher concentrations in these tumors. Moreover, in a mouse model for chronic lymphatic leukemia (CLL), a type of blood cancer, IL4I1, was shown to promote cancer through its effects on the immune system.
“In animals that do not produce IL4I1 in the tumor environment due to genetic alterations, the immune system is significantly more successful in preventing the cancer from progressing,” noted study author Martina Seiffert, PhD, a team leader at DKFZ.
Senior study investigator Christiane Opitz, PhD, a group leader at DKFZ, concluded by stating that “IL4I1 has great potential as a target for drugs. So far, drugs that inhibit enzymes of the tryptophan metabolism have failed in clinical trials because the tumors did not respond to them. However, the role of IL4I1 has so far been disregarded, and this enzyme has not yet been tested as a target molecule.”