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

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: FRONTIERS IN ONCOLOGY; v. 8, JUN 12 2018.
• Web of Science Citations: 6

Abstract

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)

• FAPESP's process: 14/16412-9 - Mechanisms of clock genes thermo-modulation in peripheral tissue of mammals: role of TRP channels
• Grantee: Maria Nathália de Carvalho Magalhães Moraes Figueira Borges
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/24337-4 - Clock genes modulation by UVA/blue light stimulation in normal melan-A and transformed B-16 melanocytes
• Grantee: Leonardo Vinícius Monteiro de Assis
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/27287-0 - Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness
• Grantee: Gabriela Sarti Kinker
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/50214-4 - Biological clock setting by light and temperature: phylogenetic aspects
• Grantee: Ana Maria de Lauro Castrucci
• Support type: Research Projects - Thematic Grants