IFNλ4 cell surface accumulation establishes localized innate immune environment and influences cancer risk 2310095

Abstract Introduction Interferon lambda 4 (IFNλ4) is a type III interferon encoded by IFNL4 at the 19q13.2 region. Up to 50% of people carry the rs368234815-ΔG allele in IFNL4 exon 1 and can produce functional IFNλ4 protein. IFNλ4 production (the ΔG allele) is associated with impaired HCV clearance and increased liver and prostate cancer risk. In contrast, results from the Ovarian Cancer Association Consortium and FinnGen suggest that the ΔG allele strongly protects against mucinous ovarian cancers and cysts. Here, we aimed to characterize IFNλ4 effects related to these protective associations. Methods Differential expression analyses after IFNλ4 induction in primary human hepatocytes or HepG2 (hepatocellular carcinoma) identified pathways likely relevant to mucin production, ovarian cysts, and cancer. To determine how IFNλ4 might drive cyst or tumor formation, we measured IFNλ4 overexpression effects on apoptosis in HepG2 and HEY-T30 (ovarian carcinoma) and observed IFNλ4 intercellular localization and cell surface interactions using confocal microscopy and western blot. Results Differential expression analyses revealed that IFNλ4 induced IRF1, a transcriptional regulator with tumor suppressor functions, as well as several mucin genes. Consistent with IRF1 upregulation, IFNλ4 overexpression induced apoptosis in vitro. Confocal and western blot analyses of cell surface interactions revealed accumulation of secreted IFNλ4 on the producer cell surfaces and transfer to adjacent cells. Conclusion IFNλ4 induction of IRF1, apoptosis, and mucin production may prevent cysts and mucinous cancer in the ovary, explaining the genetic associations. Cell surface accumulation, potentially facilitated by upregulated mucin production, may allow IFNλ4-producing cells to restrict signaling to only adjacent cells. This suggests a role for IFNλ4 in eliciting localized immune responses, thereby targeting cancerous cells or pathogens while preventing widespread inflammation that can damage sensitive microenvironments like in the ovary. Funding Source n/a Topic Categories Cytokines and Chemokines and their Receptors (CCR)