DNA damage (red) turns on NKG2D ligands (left) that make the cells more sensitive to killing by T cells (right).


New research from Stephan Gasser, David Raulet (University of California, Berkeley, CA), and colleagues suggests that immune cells recognize tumors based on their damaged DNA.

Immune cells have been shown to kill certain tumor cells. Unlike pathogens, however, cancer cells lack the tags that mark them as foreign and thus possibly dangerous. “What property of a tumor could the innate immune system recognize?” Raulet wondered. “Most things cancer cells do, normal cells do too.”

Raulet and colleagues turned to the DNA damage response pathway. “This is a basic cell process,” he says, “that recent evidence suggests is triggered in cancer cells.” The DNA damage response is known for inducing cell cycle arrest and, if the damage is extensive, apoptosis. Now, the group shows that the pathway also induces activators of immune cells.

In nontumor cells, damaging agents that cause DNA breaks or stalled replication forks induced ligands that are known to be recognized by the immune cell receptor NKG2D, which is found on T cells and natural killer cells. A tumor cell line expressed NKG2D ligands constitutively. In both cases, ligand expression required the damage recognition kinases, ATM and ATR, and downstream kinase Chk1.

The NKG2D ligands made cells more sensitive to killing by natural killer cells in vitro. The authors earlier reported that transfecting NKG2D ligands into tumor cells that lack them leads to tumor rejection and recently found that blocking NKG2D reduced tumor rejection. The group has now created mice lacking NKG2D to examine its effects on natural tumorigenesis. Other immune receptors might also be involved, but, as their ligands are not characterized, it will take time to examine all the possibilities.

The efficacy of the damage response in preventing cancer progression is not known, but the findings suggest that part of the success of chemotherapy and radiotherapy might be due to the increased expression of ligands that activate immune cells. Perhaps combining chemotherapy with infusions of immune cells might have a much greater effect than does either separately.


Gasser, S., et al. 2005. Nature. doi:.