Expression of the Circadian Clock Gene BMAL1 Positively Correlates With Antitumor Immunity and Patient Survival in Metastatic Melanoma

Autor(es)

Monteiro de Assis, Leonardo Vinicius ^[1] ; Kinker, Gabriela Sarti ^[2] ; Moraes, Maria Nathalia ^[1] ; Markus, Regina P. ^[2] ; Fernandes, Pedro Augusto ^[2] ; de lauro Castrucci, Ana Maria ^{[3, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Comparat Physiol Pigmentat, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Neuroimmunemodulat, Sao Paulo - Brazil

^[3] Univ Virginia, Dept Biol, Charlottesville, VA - USA

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN ONCOLOGY; v. 8, JUN 12 2018.
• Citações Web of Science: 6

Resumo

Introduction: Melanoma is the most lethal type of skin cancer, with increasing incidence and mortality rates worldwide. Multiple studies have demonstrated a link between cancer development/progression and circadian disruption; however, the complex role of tumor-autonomous molecular clocks remains poorly understood. With that in mind, we investigated the pathophysiological relevance of clock genes expression in metastatic melanoma. Methods: We analyzed gene expression, somatic mutation, and clinical data from 340 metastatic melanomas from The Cancer Genome Atlas, as well as gene expression data from 234 normal skin samples from genotype-tissue expression. Findings were confirmed in independent datasets. Results: In melanomas, the expression of most clock genes was remarkably reduced and displayed a disrupted pattern of co-expression compared to the normal skins, indicating a dysfunctional circadian clock. Importantly, we demonstrate that the expression of the clock gene aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) positively correlates with patient overall survival and with the expression of T-cell activity and exhaustion markers in the tumor bulk. Accordingly, high BMAL1 expression in pretreatment samples was significantly associated with clinical benefit from immune checkpoint inhibitors. The robust intratumoral T-cell infiltration/activation observed in patients with high BMAL1 expression was associated with a decreased expression of key DNA-repair enzymes, and with an increased mutational/neoantigen load. Conclusion: Overall, our data corroborate previous reports regarding the impact of BMAL1 expression on the cellular DNA-repair capacity and indicate that alterations in the tumor-autonomous molecular clock could influence the cellular composition of the surrounding microenvironment. Moreover, we revealed the potential of BMAL1 as a clinically relevant prognostic factor and biomarker for T-cell-based immunotherapies. (AU)

• Processo FAPESP: 14/16412-9 - Mecanismos de termo-modulação de genes de relógio em tecidos periféricos de mamíferos: papel dos canais TRP
• Beneficiário: Maria Nathália de Carvalho Magalhães Moraes Figueira Borges
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/50214-4 - Mecanismos de ajuste do relógio por luz e temperatura: aspectos filogenéticos
• Beneficiário: Ana Maria de Lauro Castrucci
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/27287-0 - Caracterização do sistema melatonérgico de gliomas humanos e sua implicação sobre o grau de agressividade e invasibilidade tumoral
• Beneficiário: Gabriela Sarti Kinker
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/24337-4 - Mecanismos de modulação de genes de relógio em melanócitos normais (melan-A) e transformados (melanoma B16-F10) por UVA e luz azul
• Beneficiário: Leonardo Vinícius Monteiro de Assis
• Linha de fomento: Bolsas no Brasil - Doutorado Direto