Interleukin-4 modulates type I interferon to augment anti-tumour immunity

Despite advances in immunotherapy, metastatic melanoma remains a significant therapeutic challenge due to the complexity of the tumour microenvironment. Intratumoural type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumour growth in some contexts. We investigated this further by engineering murine B16 melanoma cells to overexpress various IFN-I subtypes, where a spectrum of outcomes was observed. Characterisation of these tumours by RNA-sequencing revealed a tumour immune phenotype, where potent IFN-I signalling concomitant with diminished type 2 inflammation failed to confer durable tumour control. T cell-mediated rejection of these tumours was restored by introducing interleukin (IL)-4 into the tumour microenvironment, either through ectopic expression or in a pre-clinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting anti-tumour immunity, which could be harnessed to target and stratify solid tumours that are non-responsive to frontline therapies. Bulk RNA-seq profiling of whole melanoma B16-GFP, B16-IFNA4 and B16-IFNA9 tumours harvested 8 days post-engraftment (n=10 per group).