RESUMEN
Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Factor 1 Regulador del Interferón/metabolismo , Factores Reguladores del Interferón/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Factores de Transcripción SOXE/metabolismo , Animales , Apoptosis , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Quimioterapia Combinada , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Factor 1 Regulador del Interferón/genética , Factores Reguladores del Interferón/genética , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Pronóstico , Factores de Transcripción SOXE/genética , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
MITF and MYC are well-known oncoproteins and members of the basic helix-loop-helix leucine zipper (bHLH-Zip) family of transcription factors (TFs) recognizing hexamer E-box motifs. MITF and MYC not only share the core binding motif, but are also the two most highly expressed bHLH-Zip transcription factors in melanocytes, raising the possibility that they may compete for the same binding sites in select oncogenic targets. Mechanisms determining the distinct and potentially overlapping binding modes of these critical oncoproteins remain uncharacterized. We introduce computational predictive models using local sequence features, including a boosted convolutional decision tree framework, to distinguish MITF versus MYC-MAX binding sites with up to 80% accuracy genomewide. Select E-box locations that can be bound by both MITF and MYC-MAX form a separate class of MITF binding sites characterized by differential sequence content in the flanking region, diminished interaction with SOX10, higher evolutionary conservation, and less tissue-specific chromatin organization.