An intriguing study reports that the immune system’s elimination of cancer cells varies greatly depending on the time of day, a finding that could have major implications for improving cancer treatments.
All living things evolved to coordinate their activities with the day-night cycle associated with the Earth’s rotation. These “circadian rhythms” (from Latin circa “about” and diem “day”) were chosen in evolution because they allow physiological functions to be synchronized to a specific time of day in order to optimize their efficiency.
Almost all of our physiological systems, be it blood pressure, body temperature, hormone levels or metabolism, have their own circadian rhythms.
For example, liver cells start producing digestive enzymes a few hours before waking up, so these enzymes are already available to process breakfast foods.
growth differences
Immunity also shows significant diurnal variations, characterized by diurnal variations in the levels of several immune cells in the blood.
Because this immune system is the main mechanism for eliminating cancer cells that spontaneously form every day of our lives (called immune surveillance), these fluctuations suggest that cancer therapies that exploit the activity of cells may vary in effectiveness depending on when they are administered.
This is particularly evident from the spectacular results of a study recently published in Nature (1).
Using mice as models, the researchers first observed that implanting melanoma cells at dawn, just at the end of their active period (the mice are nocturnal and dormant during the day), produced much larger tumors than when the same cancer cells were injected in the late afternoon or early evening , just at the end of their rest period.
This large difference in tumor growth is also observed when the animals are kept in the dark for the duration of the experiment, strongly suggesting that tumor development follows an intrinsic circadian rhythm, independent of light.
immune variations
These circadian fluctuations in tumor growth appear to be inherently immune, as the same experiment, but this time performed in mice without an immune system, shows no difference in tumor growth depending on when the cancer cells are implanted.
A more detailed analysis of tumors confirms this crucial role of immunity.
The researchers discovered that the slower-growing tumors (just implanted at the end of the dormant phase) contained larger amounts of cytotoxic T-lymphocytes, the famous killer T-cells specialized in eliminating cancer cells.
This accelerated recruitment of killer cells is due to greater mobilization of dendritic cells (DC) to the site of tumors.
These dendritic cells are absolutely necessary for the activation of killer cells, so by being more numerous and more active at the site of implantation of tumors, they can attract larger numbers of killer cells and thus eliminate cells more effectively.
The study shows that these dendritic cells are the element responsible for the circadian rhythm of the anti-cancer immune response, since it is precisely at the end of the quiescent phase that these cells express higher levels of a receptor (CD80) that is essential for the activation of killer cells. All of this is very complex, but the important point is that the immune cells’ natural molecular clock allows these cells to respond more effectively to the presence of cancer cells if they come into contact with them at any point in the day.
Therapeutic Implications
These results therefore raise the interesting possibility that the effectiveness of cancer therapies that rely on activation of the immune system (immunotherapy) may be highly dependent on when these treatments are administered.
As the authors mention, it is relatively easy to control this parameter in the clinic, and it is hoped that prospective clinical trials will be initiated to determine what time of day treatment is associated with the greatest improvement in antitumor response and clinical condition of the patients.
(1) Wang C. et al. Dendritic cells control circadian anti-tumor immune responses. Naturepublished on December 5, 2022.