Clock Disruption Accelerates Colorectal Cancer and Promotes Immunosuppression

ABSTRACT Colorectal cancer (CRC) is the third most diagnosed cancer in the United States. With increasing public knowledge of cancer risk factors and screening, the incidence of CRC has steadily decreased in individuals over the age of 50 over the last several decades. However, the incidence of CRC in younger populations has been

on the rise. Individuals under the age of 50 are increasingly afflicted by light-at-night exposure, night-shift work, and erratic eating patterns, which are known to disrupt the circadian clock. Importantly, disruption of circadian

rhythms is a known risk factor for CRC. Therefore, it is likely that disruption of the circadian clock is a contributing factor for the alarming increase in early-onset CRC cases. This emerging link between the circadian clock and cancer has enormous potential for cancer prevention strategies. While causal links are clear, the underlying

mechanism of how the circadian clock impinges on antitumor immunity to create a permissive environment for tumorigenesis is unknown. The goal of this project is to understand how both genetic and environmental circadian clock disruption alter the immune landscape to promote tumorigenesis. Our preliminary findings suggest that

disruption of the circadian clock promotes inflammation and alters host immunity. Based on these findings, we hypothesize that clock disruption promotes inflammation to create an immunosuppressive microenvironment suitable for cancer initiation and progression. This central hypothesis will be addressed

with the following Specific Aims. Aim 1 will determine how clock disruption alters the in vivo immune landscape through the activation of MDSCs and the suppression of cytotoxic CD8+ T cells. Aim 2 will define the molecular mechanism for how clock disruption impacts host immunity to accelerate tumorigenesis through the Wnt

signaling pathway and MYC. The outcome of our findings will define the mechanistic underpinning linking disruption of the circadian clock to altered host anti-tumor immunity. The long-term goal of this study is to improve cancer prevention and treatment through lifestyle and pharmacological manipulation of the link between the

circadian clock and the immune system.