Shifting DNA Damage Dynamics May Temper Immune Response to Cancer

DNA damage within a cell is known to trip an alarm system that attracts the notice of immune cells, which then descend on the cell, whether it has been infected, deranged by cancer, or disabled by chemotherapy or radiation. Curiously, cells that have been subjected to radiation seem to benefit from a sort of grace period. Days may pass before immune cells show up to tumors that have survived the effects of toxic therapies.

The reasons behind this delay have been unclear, but now that they have been revealed by a new study, they may point to new therapeutic strategies, particularly those that combine genotoxicity and immune checkpoint inhibitors.

The new study comes from the Perelman School of Medicine at the University of Pennsylvania. There, researchers led by Roger Greenberg, M.D., Ph.D., detailed the events that unfold between DNA damage and the immune response.

“Having solved what cues immune cells to arrive at cancer cells with DNA damage in the first place, we can apply that information to design better treatments,” said Dr. Greenberg. “This tactic aims to improve a patient’s response to treatment using the immune system at the same time as inhibitors to keep cancer cells on track to replicate until cell death sets in.”

Cancer is essentially a disease of the cell replication cycle. The goal of treating the disease is to permanently kill off the cells that replicate with abandon without any molecular brakes. Chemotherapy and radiation cause breaks in DNA and eventually death, even in these out-of-control cells. Within minutes after being exposed to treatment, cancer cells call on DNA-repair proteins to counteract the damage wrought by these treatments. Days later, immune cells show up to tumors to assist further in beating back cells that have survived the effects of the toxic therapies.

If a cell’s DNA is damaged, it stalls for about 24 hours at a point in the cell replication cycle just prior to entering a phase that leads to cell division. Cells resume dividing as they eventually overcome their wounds, and this leads to activation of signals that attract the immune system.

Dr. Greenberg’s team decided to study how it is that this immune response can be delayed for days, in contrast to the acute DNA-damage responses that occur in minutes to hours. What they discovered led them to suggest an innovative approach to the design of combination therapies against cancer.

The team’s findings appeared in the journal Nature, in an article entitled “Mitotic Progression Following DNA Damage Enables Pattern Recognition within Micronuclei.” This article explains how an examination of the “dichotomous kinetics” observed for DNA-damage responses led to the clarification of the rate-limiting steps that are essential for DNA-damage-induced inflammation.

“Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP–AMP synthase (cGAS),” wrote the article’s authors. “Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)–cGAS impaired interferon signaling.”

Essentially, DNA damage from cancer therapies causes small packages of DNA from the nucleus to form in the cytoplasm when cells divide after experiencing DNA damage from radiation or chemotherapies. These out-of-place micronuclei tend to rupture, exposing DNA within the cytoplasm to a special surveillance protein. This watchdog molecule is typically activated when invaders such as viruses are detected as foreign DNA in the cytoplasm. The antimicrobe alarm incites an immune response, hailing immune cells to attack micronuclei-filled cancer cells.

The team demonstrated that inhibiting cells from progressing to later cell-division stages prevented micronuclei from forming and strongly reduced immune responses to cancer cells that had been treated with radiation.

Overall, the Nature study reveals that changes in how fast or slow a cancer cell progresses through cell division is an important consideration for cancer therapies that combine DNA damage and immune checkpoint inhibitors.

“Our work allows for the development of rational strategies to increase immune response to enhance patients’ sensitivity to radiation,” asserted Dr. Greenberg. “This approach would combine drugs that damage DNA and inhibit immune checkpoints with those that promote cell division by interfering with the factors that delay cell division in response to DNA damage.”