The NF1 tumor suppressor regulates PD-L1 and immune evasion in melanoma

Abstract

Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively. Compared to mutant BRAF and NRAS, the role of NF1 loss in melanoma remains understudied. NF1 has a RAS GTPase-activating protein (GAP) function; however, studies also support NF1 RAS-independent tumor-suppressor functions. Recent reports indicate that patients with NF1 mutant melanoma have high response rates to anti-PD-1 immune checkpoint inhibitors (ICIs) for reasons that are not entirely clear. Here, we present data demonstrating that NF1 interacts with PD-L1. Furthermore, NF1 loss in melanoma lines increases PD-L1 cell surface expression through a RAS-GAP-independent mechanism. Co-culture experiments demonstrate that NF1 depletion in melanoma increases resistance to T cell killing, which can be abrogated with anti-PD-1/PD-L1 ICIs. These results support a model whereby NF1 loss leads to immune evasion through the PD-L1/PD-1 axis, providing support for the examination of anti-PD-1 therapies in other NF1 mutant cancers.

Keywords: CP: Cancer; NF1; PD-L1; anti-PD-1; cancer; immune checkpoint blockade; immune checkpoint inhibitors; immune evasion; melanoma; tumor suppressor.