Circadian and Immunity Cycle Talk in Cancer Destination: From Biological Aspects to In Silico Analysis

Abstract

Cancer is the leading cause of death and a major problem to increasing life expectancy worldwide. In recent years, various approaches such as surgery, chemotherapy, radiation, targeted therapies, and the newest pillar, immunotherapy, have been developed to treat cancer. Among key factors impacting the effectiveness of treatment, the administration of drugs based on the circadian rhythm in a person and within individuals can significantly elevate drug efficacy, reduce adverse effects, and prevent drug resistance. Circadian clocks also affect various physiological processes such as the sleep cycle, body temperature cycle, digestive and cardiovascular processes, and endocrine and immune systems. In recent years, to achieve precision patterns for drug administration using computational methods, the interaction of the effects of drugs and their cellular pathways has been considered more seriously. Integrated data-derived pathological images and genomics, transcriptomics, and proteomics analyses have provided an understanding of the molecular basis of cancer and dramatically revealed interactions between circadian and immunity cycles. Here, we describe crosstalk between the circadian cycle signaling pathway and immunity cycle in cancer and discuss how tumor microenvironment affects the influence on treatment process based on individuals' genetic differences. Moreover, we highlight recent advances in computational modeling that pave the way for personalized immune chronotherapy.

Keywords: cancer immunity cycle; circadian cycle; computational biology; immunotherapy.

Figure 1

Intracellular circadian cycle pathway. The accumulating PER and CRY proteins bind to CLOCK/BMAL1 and switch them from an activated state to an inhibited state, blocking the transcriptional activity of downstream genes. ROR/REV-ERB regulates the main feedback loop by acting on RORE.

Figure 2

Effect of the circadian cycle on the main process of cancer such as cell cycle and immune behavior.

Figure 3

Cross talk between immunity cycle and circadian cycle genes; Recognizing, destroying, and releasing antigens from cancer cells are all part of this process. When NK cells are activated in tumor locations and come into direct contact with malignant cells, they kill them without the need for any kind of pre-exposure. In effector T cells, the circadian clock (ROR, PER1, CRY2, and BMAL1) adversely regulates PD-1 expression. CTLA-4 and PD-L1 are similarly negatively regulated by BMAL1 in effector T cells. IFN-γ, granzyme B, and perforin production by NK cells can be enhanced by PER-1 and BMAL1.

Figure 4

Our connection between the immune system and circadian rhythms could lead to a new area in cancer treatment. Using cellular and molecular data such as Omix data and pathology images, analyzing them, and establishing a network between these two cycles, determines the appropriate treatment for each person based on the administration time and the type of drug.

Figure 5

Systems pharmacology in cancer is a new field that has a significant role in the design, discovery, and repositioning of drugs due to the growth of basic cancer studies and the existence of accurate genetic and protein data and reliable data on drugs. These data, along with accurate bioinformatics models, can predict drug effects very well.