Cancer cells can appear anywhere in our bodies at any time. Fortunately, they are almost always recognized and eliminated by our immune system.
Immunotherapy is a type of cancer treatment that can help the immune system fight cancer.
Scientists have discovered that the effectiveness of immunotherapy is influenced by circadian rhythms; performing it at the appropriate time can result in better treatment outcomes.
The Impact of Timing on the Immune System’s Ability to Eliminate Cancer Cells
The circadian clock in our bodies operates on a 24-hour cycle following the laws of nature, supporting countless physiological processes. For example, the liver cells produce digestive enzymes prior to breakfast, ensuring their availability during the digestive process of the upcoming meal.
According to a recent article in Nature, the immune system is also influenced by the circadian clock, and its ability to identify and eliminate cancer cells varies depending on the time of day.
In December 2022, scientists from the University of Geneva and the Ludwig Maximilian University of Munich published a study in Nature illustrating a highly actionable approach to improving the effectiveness of cancer treatment: Administering immunotherapy at the right time can potentially achieve significantly better treatment outcomes.
In other words, simply changing the time of treatment administration could greatly improve its effectiveness. On the other hand, ignoring the timing could mean missing a valuable opportunity to effectively fight cancer, according to the study.
Researchers first injected cancer cells into healthy mice at different times of day and found that the timing of injection affected the development of cancer; mice injected with cancer cells during their rest period had slower tumor growth, while those injected during their active period had faster tumor growth.
Interestingly, such a difference was not observed in immunocompromised mice, which prompted the researchers to conduct a more detailed investigation into the role of immune cells.
They observed that slow-growing tumors contained more cytotoxic T cells, a type of immune cell that can kill cancer cells, compared to fast-growing tumors.
In addition to killer T cells, there is another critical type of immune cell called dendritic cells, which takes up cancer cell components, as well as transmits and activates killer T cells.
In a metaphorical sense, dendritic cells act as sentinels that detect and capture images of the criminals (cancer cells). These images are then transmitted to the heavily armed special forces (killer T cells), who enter combat mode and eliminate the cancer cells with precision.
Resting Immune Cells Fight Cancer Better
This study also reported that compared to mice injected with cancer cells during their active period, mice injected with cancer cells during their resting period not only had more dendritic cells in their bodies, but these cells were also more “alert”—expressing a higher amount of proteins that can effectively activate cytotoxic T cells.
This means that dendritic cells (that act as sentinels) produced during the organism’s resting period not only exist in greater numbers, but are also more active in promoting the transition of killer T cells (that act as special forces) from standby to combat mode.
However, when the circadian clock of dendritic cells in mice was disrupted and cancer cells were injected, the growth of tumors was no longer affected by the time of injection. According to the researchers, this suggests that the activation of dendritic cells’ anti-cancer efficacy is regulated by the circadian clock.
Cancer vaccines are also considered a type of immunotherapy that contains specific components of cancer cells designed to trigger the immune cells to attack malignant tissue. Therefore, the researchers speculate that administering cancer vaccines at specific times of the day may increase their efficacy in cancer treatment.
Optimal Cancer-Fighting Time in Human Body
It is worth noting that this study used mice for animal experiments, and mice are nocturnal animals that are active at night, with their circadian rhythms opposite to that of humans.
The researchers stated in the report that “the time of day for the administration of any other treatment involving immune system activation may also matter.”
The researchers also analyzed a human study published in the Clinical Cancer Research journal in 2005, which administered cancer immunotherapy through the injection of cancer vaccines into skin cancer patients. The data showed that the treatment was more effective when administered in the morning, as compared to the afternoon, as there was an increase in specific T cells in the patients’ blood.
In fact, numerous studies have found that immunotherapy is more effective during the day.
The most common form of immunotherapy is immune checkpoint inhibitors.
In November 2021, researchers from the Winship Cancer Institute at Emory University in Atlanta, Georgia, published a study in The Lancet in which 299 patients with advanced melanoma were treated with immune checkpoint inhibitors. The researchers found that patients who received injections in the evening had a less robust adaptive immune response compared to those who received injections during the day.
Therefore, they suggested that the best time to administer immune checkpoint inhibitors to patients with advanced melanoma is before 3 p.m. in the afternoon.
However, there are studies with slightly different findings.
In a study published in 2020, 30 patients with metastatic renal cell carcinoma were divided into three groups and treated with interleukin-2 at different time periods (5:00–13:00, 13:00–21:00, and 21:00–5:00).
Interleukin-2 injection is a nonspecific immunotherapy aimed at enhancing the immune response in cancer patients.
The results showed that patients who received treatment in the morning and at night had a longer median overall survival compared to those who received treatment in the afternoon and evening, but the study indicated that this difference was not significant.
Fewer Side Effects With Morning Treatment
In another experiment, 95 patients with metastatic Non-Small Cell Lung Cancer (NSCLC) were divided into a “morning group” and an “afternoon group” based on a cutoff time of 12:55 p.m., and were injected with immune checkpoint inhibitors.
The results showed that patients in the morning group had lower rates of fatigue, anorexia, and myalgia.
It is worth noting that the median progression-free survival (PFS) for the morning group was about 11 months, compared to nearly three months for the afternoon group; whereas the median overall survival (OS) for the morning group was about 34 months, compared to roughly 10 months for the afternoon group.
Based on the findings, the researchers concluded that morning treatment not only had lower toxicity compared to afternoon treatment but was also four times as effective.
Christoph Scheiermann, an author of the aforementioned December 2022 study published in Nature, as well as a professor at the Department of Pathology and Immunology, the Geneva Centre for Inflammation Research (GCIR), and the Centre for Translational Research in Onco-Hematology (CRTOH) at the UNIGE Faculty of Medicine, believes that “immune activation fluctuates throughout the day, and peaks in the late behavioral resting phase.”
Regarding the study conducted by the University of Geneva and the Ludwig Maximilian University of Munich, researchers from the Charité Universitätsmedizin Berlin, Institute of Medical Immunology, commented that strategically choosing the timing of interventions, such as administering treatments during the period of maximum efficacy and minimum side effects, could improve the efficacy and safety of therapies. They also stated that “we should not miss this opportunity.”