The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics

Abstract

The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.

Keywords: Cancer; Circadian; Clock gene; Glucocorticoid; Immune checkpoint inhibitor; Immuno-oncology.

Fig. 1

Circadian markers and their influences on immune-oncology pathways. Diagram represents a simplified depiction highlighting immune cells and receptors of interest. Circadian effects supported by experimental evidence are depicted, with connectors representing the direction of relationships (i.e., arrows represent positive or upregulatory relationships, flat connectors represent negative or inhibitory relationships). Not depicted, disruption or tumor reprogramming of circadian gene signals has been associated with tumor immunophenotype patterns and glucocorticoids have been implicated in poorer response to anti-PD-(L)1 therapy. *“Clock Index” refers to a combined index score of BMAL1, PER1/2/3, CRY1/2, and CLOCK expression levels across multiple cancer types [56]