Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer

Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinoma (BCC) has low immunogenicity. Here, we demonstrate that BCC's low immunogenicity is associated with epigenomic suppression of antigen presentation machinery reminiscent of its cell of origin. Primary BCC had low T cell infiltrates and low human leukocyte antigen class I (HLA-I) expression compared with cutaneous squamous cell carcinoma (SCC) and normal keratinocytes. Forkhead box C1 (Foxc1), a regulator of quiescence in hair follicle stem cells, was expressed in BCC. Foxc1 bound to promoter of interferon regulatory factor 1 and HLA-I genes, leading to their deacetylation and reduced expression. A histone deacetylase inhibitor, entinostat, overcame Foxc1's effect and upregulated HLA-I in BCC. Topical entinostat plus imiquimod immunotherapy blocked BCC development in mice. Collectively, our findings demonstrate that low BCC immunogenicity is associated with a stem-like quiescent program preserved in the tumor cells, which can be blocked to enable BCC immunotherapy.