Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.
Publication Title
Nat Commun
Document Type
Article
Publication Date
8-4-2024
Keywords
oregon; chiles; portland; 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
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.
Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
Specialty/Research Institute
Pathology & Laboratory Medicine
Specialty/Research Institute
Surgery
DOI
10.1038/s41467-024-50881-1
