A new study led by a multidisciplinary research team at the University of California (UC), Irvine, demonstrates that the circadian clock can be leveraged to enhance the efficacy of checkpoint inhibitor cancer therapy. The findings provide deeper insights into the intricate relationship among the circadian clock, immune regulation, and tumor development and reveal that a therapeutic approach optimizing time-of-day delivery based on an individual’s unique circadian patterns offers new avenues for prevention and treatment.
The findings are published in Nature Immunology in an article titled, “Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.”
“The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance,” the researchers wrote. “Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells.”
The researchers discovered that disruption of the internal clock in the epithelial cells lining the intestine alters the secretion of cytokine proteins, leading to heightened inflammation, increased numbers of immunosuppressive myeloid cells, and cancer progression. Their findings suggest that providing immunotherapy at the time of day when these immunosuppressive myeloid cells are most abundant significantly enhanced the efficacy of immune checkpoint blockades in solid tumors.
“Disruption of the internal biological pacemaker is an inherent aspect of modern society that may contribute to the rising incidence of many cancer types. We found that proper regulation of circadian rhythms is necessary to suppress inflammation and support peak immune function,” said corresponding author Selma Masri, PhD, UC Irvine associate professor of biological chemistry. “Understanding precisely how circadian disruption promotes disease progression could lead to behavior modification to reduce cancer risk.”
“As we enhance our understanding of the fundamental mechanism of circadian regulation of immunity, we will be able to harness the power of the body’s natural rhythms to fight cancer and develop more personalized and effective treatment strategies,” said lead author Bridget Fortin, a UC Irvine doctoral student in the department of biological chemistry.
While this study represents a significant step forward in defining circadian control of anti-tumor immunity, the team believes future research should focus on exploring additional factors and cell types influencing time-of-day response to checkpoint inhibitor therapy.
