VISTA enforces a clathrin adapter-mediated endosomal trafficking checkpoint in triple negative breast cancer
Introduction
VISTA is a negative immune checkpoint molecule and cancer therapy target that is now under evaluation in multiple early-phase human clinical trials. Understanding the mechanisms of VISTA activity are critical to inform the clinical development of this new, important class of VISTA-blocking therapies. To this end, we report for the first time, a molecular framework for understanding VISTA’s mechanism of action that should have reverberations across the fields of immunology, cancer, and cell biology.
Methods
We use human tumor specimens, different cancer cell lines, and mouse models to investigate the role of VISTA in breast cancer.
Results
Triple-negative breast cancer (TNBC) is characterized by clinical heterogeneity in its aggressiveness and response to immunotherapy. We identify a class of human TNBCs with high V-domain Ig-containing suppressor of T-cell activation (VISTA) expression and immunosuppressed microenvironments, yet relatively low proliferative index. Modeling of mouse and human TNBCs demonstrated that VISTA expression caused tumor-cell-intrinsic growth suppression, even in the absence of an immune system. Mechanistically, we identify the clathrin-adaptor molecules NUMB and GULP1 in complex with the VISTA intracellular NPGF motif. VISTA caused the recruitment of NUMB to EEA1+ vesicles, resulting in diminished EGFR endocytosis and trafficking. Antibodies targeting VISTA block the immune checkpoint without disrupting the endosomal checkpoint, an effect that causes VISTA+ TNBCs to be uniquely sensitive to VISTA antibodies.
Conclusion
These results identify a subset of TNBCs that should be sensitive to novel immunotherapy drugs and imply that clathrin adapter-mediated endosomal trafficking may be a new immune checkpoint mechanism.