Expression of immune checkpoint VISTA represents a differentiated state of cancer cells and plays a role in regulating actin cytoskeleton

Immune checkpoint VISTA, or VSIR, is believed to indicate a differentiated, less malignant state in cancer cells, according to a recent study. This finding challenges the notion that immune checkpoint blockade alone can effectively treat cancer, as previously thought. Researchers observed that cells with high VISTA expression tend to be less malignant compared to those with low expression.

The study identified neural stemness factors HHEX, MYOD1, and PPARG that promote VISTA expression, while oncoproteins KRAS and SOX2, as well as the embryonic neural factor SOX2, repress it. Expression of VISTA in cancer cells did not affect tumorigenicity or differentiation state, but did alter their morphology and actin cytoskeleton.

VISTA regulates a key cytoskeleton regulator, WASF2, which may interfere with signal transduction of immune response, potentially explaining why immune checkpoint blockade has had limited success in cancer therapy. The findings suggest that targeting VISTA in tumors might leave malignant cells unaffected, potentially leading to weak or ineffective treatments.

Additionally, immune checkpoints may have other roles in cells that interfere with anti-tumor immunity.