Interleukin-4 modulates type I interferon to augment antitumor immunity
Despite advances in immunotherapy, metastatic melanoma remains a considerable therapeutic challenge due to the complexity of the tumor microenvironment. Intratumoral type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumor 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. Characterization of these tumors by RNA sequencing revealed a tumor immune phenotype, where potent IFN-I signaling concomitant with diminished type 2 inflammation failed to confer durable tumor control. T cell-mediated rejection of these tumors was restored by introducing interleukin-4 (IL-4) into the tumor microenvironment, either through ectopic expression or in a preclinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting antitumor immunity, which could be harnessed to target and stratify solid tumors that are nonresponsive to frontline therapies.
Authors
- Bree Foley (ORCID: https://orcid.org/0000-0003-3826-2682)
- Belinda B. Guo (ORCID: https://orcid.org/0000-0003-2146-8561)
- Emma de Jong (ORCID: https://orcid.org/0000-0002-2501-6119)
- Anthony Bosco (ORCID: https://orcid.org/0000-0002-4335-615X)
- Jason Waithman (ORCID: https://orcid.org/0000-0003-4940-0155)
- Jesse Armitage (ORCID: https://orcid.org/0000-0002-6558-5914)
- Hannah V. Newnes (ORCID: https://orcid.org/0000-0003-1647-975X)
- Michael Serralha (ORCID: https://orcid.org/0000-0002-0121-2879)
- Vanessa S. Fear (ORCID: https://orcid.org/0000-0001-8363-6685)
- Phillip K. Darcy (ORCID: https://orcid.org/0000-0002-5303-9561)
- Katherine M. Audsley (ORCID: https://orcid.org/0000-0001-6330-8385)
- Samantha Barnes (ORCID: https://orcid.org/0000-0002-5075-6696)
- Paul A. Beavis (ORCID: https://orcid.org/0000-0002-2116-013X)
- Alistair R. R. Forrest (ORCID: https://orcid.org/0000-0003-4543-1675)
- Anthony Buzzai (ORCID: https://orcid.org/0000-0001-8295-2950)
- Matt Jones (ORCID: https://orcid.org/0000-0003-4723-3277)
- Shamini Srinivasan (ORCID: https://orcid.org/0000-0001-6858-9964)
Institutions
- University of Arizona (US)
- The University of Melbourne (AU)
- The Kids Research Institute Australia (AU)
- The University of Western Australia (AU)
- Harry Perkins Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Queen Elizabeth II Medical Centre (AU)
- Monash University (AU)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1126/sciadv.adt3618
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.18