Use the morning hours for immunotherapies

The experiment is remarkably simple—and quickly explained: Researchers led by Christoph Scheiermann at the University of Geneva injected mice with cancer cells at different times throughout the day. After two weeks, they observed tumors of varying sizes. Mice that received cancer cells in the morning developed tumors twice as large as those in mice that were injected in the afternoon. How does Scheiermann explain these striking results? “Mice are nocturnal. They wake up when it gets dark,” he says. “That’s when they ramp up their immune system.”

Increased immune readiness after waking

Intuitively—and from an evolutionary biology perspective—this makes sense. After waking up, mice enter the phase in which they move around and, for example, search for food or mates to reproduce. The likelihood of encountering pathogens is higher during this time, so it pays to increase immune readiness. With their work, Scheiermann and his team have shown that the internal clock aligned with the day–night rhythm primarily controls the behavior of two types of immune cells: dendritic cells and cytotoxic T cells.

Dendritic cells are the immune system’s bloodhounds. During the waking phase, they patrol the body in search of threats. During sleep, by contrast, they migrate to nearby lymph nodes and exchange information with other immune cells there. If dendritic cells detect something suspicious, they trigger the proliferation of cytotoxic T cells to combat the danger. “We have shown that the proliferation and mobility of cytotoxic T cells also fluctuate significantly over the course of the day,” says Scheiermann.

To demonstrate this, his team again allowed tumors to grow in mice over two weeks and then removed the tumors at different times throughout the day. Tumors removed in the evening—at the beginning of the waking phase—contained twice as many T cells that had migrated into the tumor as tumors removed in the morning. In further studies, Scheiermann’s team uncovered many important findings related to immunotherapeutic methods currently used in the clinic. All results pointed in the same direction.

Link also found in human cancer samples

Whether the researchers analyzed cancer vaccines, genetically modified T cells, or immune checkpoint inhibitors—all immunotherapeutic approaches worked best around the time of waking. This was not only true for experiments in mice. Scheiermann and his team found the same relationship in tumors from human patients. However, unlike mice, humans are active during the day. We wake up in the morning, and accordingly, treatments administered in the morning achieved better results on average than those given in the afternoon.

“Many immunotherapeutic drugs circulate in the blood for several weeks,” says Scheiermann. “How can it be that the time of administration matters so much? We still lack an understanding of the fundamental mechanisms of the immune response.” Yet when the expert in biological rhythms speaks of oscillations and fluctuations, an image of a child’s swing comes to mind: you only go higher if you shift your weight backward at the right moment. The immune system may respond to external stimuli in a similar way. If you want it to oscillate more strongly, you have to push at the right time.

Growing interest in the internal clock

Scheiermann is a basic researcher and has been investigating the sophisticated mechanisms of the internal clock for 15 years. That these mechanisms also play an important role in cancer, however, only became apparent to him and his team six years ago. “We come from a different angle,” says Scheiermann. “We are incredibly grateful for the funding, because without the willingness of the Swiss Cancer Research foundation to take risks, our project would not have been possible.” Interest in the effects of the day–night rhythm has increased in recent years, Scheiermann notes—no doubt aided by the impressive results he and his team have published.

“Today, clinicians listen to us much more closely,” says Scheiermann. Until recently, the medical community paid little attention to the exact timing at which patients received immunotherapeutic drugs. Today, a shift in thinking is taking place. Rather than ignoring these fluctuations, the field wants to exploit them. Worldwide, several clinical studies are underway to conclusively demonstrate the influence of the internal clock—and the greater effectiveness of immunotherapies in the morning hours. Scheiermann expects initial results later this year and adds: “Hopefully, many more patients will soon benefit from this as well.”