Investigation of lncRNA GRASLND in the context of melanoma differentiation and IFNy response

Abstract

Melanoma, originating from malignant melanocytes, is the leading cause of skin cancer-related deaths arises from its high metastatic potential, heterogeneity, and phenotypic plasticity. This plasticity drives tumor progression, metastasis, and therapy resistance. Immune checkpoint blockade (ICB) immunotherapy, the primary treatment for metastatic melanoma, enhances cytotoxic T lymphocyte (CTL) activity but faces challenges due to resistance. Resistance is linked to impaired HLA class I antigen presentation and loss of melanocytic differentiation antigens via phenotype switching, allowing immune evasion. Long non-coding RNAs (lncRNAs) regulate key melanoma processes, including immune escape, proliferation, metastasis, and drug resistance, but their role in melanoma plasticity remains largely unknown. This study investigated lncRNA GRASLND in melanoma, building on its known role in mesenchymal stem cells (MSCs) as an inhibitor of IFNγ signaling, a key pathway regulating HLA class I-APM and CTL immunogenicity via interaction with PKR. GRASLND was overexpressed in melanoma tumors, associated with a differentiated cell state, and linked to poor prognosis. Its knockdown induced a shift from a proliferative melanocytic state to a dedifferentiated, invasive state. GRASLND was also enriched in immune “cold” tumors and inversely correlated with immune response activation. Notably, IFNγ reduced GRASLND expression, leading to increased ISG and HLA-I expression, confirming its suppressive effect on IFNγ signaling in melanoma. The GRASLND-PKR interaction was validated, suggesting an immune evasion mechanism. Targeting this interaction may help counteract immune escape in melanoma.