Circadian disruption promotes tumor immune microenvironment remodeling favoring tumor cell proliferation

AIELLO, IGNACIO; MALENA L. MUL FEDELE; FERNANDA ROMÁN; LUCIANO MARPEGAN; CARLOS S. CALDART VALLE; JUAN J. CHIESA; DIEGO A. GOLOMBEK; CARLA FINKIELSTEIN; NATALIA PALADINO

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2020

23752548

Circadian disruption (CD) negatively impacts physiology posing a global health threat that manifests in proliferative, metabolic, and immune diseases, among others. Since outputs of the circadian clock regulate daily fluctuations in the immune response, we asked whether CD results in tumor-associated immune cell remodeling, facilitating tumor growth. Our findings show that tumor growth rate increased and latency decreased under CD conditions compared to normal light-dark (LD) schedules in a murine melanoma model. Importantly, CD induced the loss or inversion of daily patterns of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages and cytokine levels in spleen and tumor tissues. Additionally, CD induced i) deregulation of rhythmic expression of clock genes, and ii) of cyclin genes in the liver, iii) increased CcnA2 levels in the tumor, and iv) dampened expression of the cell-cycle inhibitor p21WAF/CIP1, all of which contribute to a proliferative phenotype.