Faculty, Staff and Student Publications
Publication Date
8-4-2024
Journal
Nature Communications
Abstract
Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.
Keywords
Tumor Microenvironment, Animals, ADP-Ribosylation Factor 6, Humans, Mice, ADP-Ribosylation Factors, Immune Checkpoint Inhibitors, Melanoma, Cell Line, Tumor, Cell Membrane, Interferon gamma Receptor, Receptors, Interferon, Protein Transport, Melanoma, Experimental, Mice, Inbred C57BL, Female
DOI
10.1038/s41467-024-50881-1
PMID
39098861
PMCID
PMC11298541
PubMedCentral® Posted Date
8-4-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons