NK cells killing a tumor cellNatural killer cells were originally identified as cells that spontaneously killed cancer cells. It’s been a bit surprising, then, that there’s been relatively little direct evidence that NK cells protect against spontaneous cancer.

For example, there was the study I talked about some time ago, looking at tumors in equilibrium with the immune system. There, the authors treated mice with a  carcinogen, waited until tumors stopped arising, and immunosuppressed the tumor-free survivors. 1 In most of these apparently cancer-free animals, immune suppression resulted in tumors appearing within a few weeks. This showed that the immune system can control tumors.

The interesting part (at least, the interesting part as far as NK cells are concerned) was that treatment with anti-NKG2D did not let tumors grow out; whereas shutting down T cells (with anti-CD4/anti-CD8) or interferon (with anti-IFN) did let the tumors reappear. NKG2D is an important receptor for NK cells, so the implication was that NK cells were not keeping the tumor in check, but T cells were.

Now, however, a similar set of experiments has shown that’s not necessarily true — NK cells probably are important in controlling some tumors. The paper is
Guerra, N., Tan, Y. X., Joncker, N. T., Choy, A., Gallardo, F., Xiong, N., Knoblaugh, S., Cado, D., Greenberg, N. R., and Raulet, D. H. (2008). NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28, 571-580. DOI: 10.1016/j.immuni.2008.02.016

David Raulet’s group has been one of the leaders in NK cell research, and as far as I know they are the first to have made a knockout mouse lacking NKG2D. The mice are normal and happy and actually have normal numbers of NK cells that are functional. NK cells notoriously have many ligands, which is one of the reasons it took longer to figure out NK receptor/ligand interactions than for T cells, and presumably there are enough alternatives to NKG2D that NK cells can get whatever signals they need during development. However, of course, none of the ligands for NKG2D triggered NK cells.

NK cell killing a tumor cellRather than wait for truly spontaneous tumors (which are rare enough even in mice that you need very large numbers of mice to figure out what’s going on) they crossed the NKG2D -/-mice with a couple of transgenic lines that are highly cancer-prone. They also tried treating the mice with carcinogens, as was done in the Koebel et al study I mentioned earlier.

The carcinogen-treated NKG2D knockout mice got no more tumors than did wild-type mice — so that’s exactly consistent with the previous experiment. However, the “spontaneous” tumor transgenic models showed a big difference. The NKG2D knockouts had much earlier, more aggressive tumors than did the wild-type mice.

As well as evidence for cancer equilibrium, the Koebel et al paper showed evidence for immunoediting. 2 That is, tumors that grow in the presence of a healthy immune system are resistant to the immune response — they have been selected for immune invisibility or resistance. By comparison, tumors that grow in immune deficient mice are much more immunogenic — they haven’t had to develop immune resistance.

In one of the two transgenic systems, the NKG2D knockout mice showed the same thing: Their tumors were more likely to have NKG2D ligands than the wild-type mice. “These data suggest that NKG2D-dependent immunoselection (or editing) favors loss of NKG2D ligands on early-arising, aggressive tumors.”

But in the other tumor system no such evidence was seen; NKG2D ligands were just as prevalent:

There was no indication in this survey that expression of NKG2D ligands was selected against in Klrk1+/+ mice, despite the clear evidence that NKG2D-mediated surveillance is operative for these lymphomas. These data suggest that evasion of NKG2D-mediated surveillance by Eμ-myc-induced lymphomas occurs by mechanisms that do not depend on loss of NKG2D ligands.

So it seems that NK immune surveillance is much more complicated than the (already very complicated) T cell immune surveillance of tumors:

Taken together, these data suggest that the role of NKG2D-dependent surveillance differs in the three types of tumors studied here. In the case of early-arising prostate carcinomas in TRAMP mice, many of the tumors are eliminated, and the few that are not eliminated evade surveillance by extinguishing expression of NKG2D ligands. In the case of Eμ-myc lymphomas, it appears that the emerging tumors are mostly NKG2D sensitive, but a fraction of tumors escape NKG2D surveillance without losing NKG2D ligands. … The final category is represented by late-arising prostate carcinomas, which appear to be generally refractory to NKG2D-dependent surveillance.

But the bottom line is that NK cells do control some tumors. That’s not a surprise, because it’s pretty much been the assumption for a long time, but it’s reassuring to get evidence for it.


  1. Koebel, C. M., Vermi, W., Swann, J. B., Zerafa, N., Rodig, S. J., Old, L. J., Smyth, M. J., and Schreiber, R. D. (2007). Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903-907.[]
  2. Of course, this wasn’t the first evidence for immunoediting.[]