Following the recent report that mice with several genomic copies of Trp53 are resistant to cancer formation, comes the discovery that a genetic trait can induce resistance to or regression of cancer in mice by soliciting an immune response. Amazingly, Zheng Cui and colleagues discovered this trait by accident, and have analysed it further.

In examining the response to intraperitoneal injection of S180 cells — which results in ascites fluid, metastasis and death within 3–4 weeks — the authors discovered a male mouse that was resistant to ascites formation. When bred with S180-sensitive mice, ∼40% of the F1 progeny and later generations were also resistant, indicating that the trait was dominant to the wild type and only one locus is thought to be responsible. This was independent of sex, so the trait is presumably located on an autosome.

Interestingly, the response does vary according to age. Mice that are 6 weeks old on first injection of S180 cells are completely resistant to ascites formation; however, as mice age, their response changes from resistance to regression. If the mice are 22 weeks old on first injection, almost all have switched to a regression response — ascites fluid develops over the first two weeks, but then disappears within 24 hours. This indicates that the anticancer mechanism takes a longer time before it is engaged in older animals, but once it has been engaged, mice become completely resistant to tumour formation.

So how is this response manifested? The authors analysed peritoneal cavity washes following injection of S180 cells, and discovered that a resistant mouse was capable of destroying 20 million cancer cells within 12 hours. A large number of leukocytes migrate into the peritoneal cavity within 6–12 hours, but disappear after the cancer cells are destroyed. The immune cells seem to form rosettes around the cancer cells, and many of the cancer cells have ruptured membranes, indicative of a cytolytic event.

T cells have long been thought to mediate the anticancer immune response, but the resistance can be bred into athymic nude mice that do not possess mature T cells and remain ascites-free following injection of S180 cells. This indicates that resistance might require other immune components, and preliminary analysis reveals that these are likely to be part of the innate immune response, such as neutrophils, macrophages and natural-killer cells.

The ability of adoptively transferred leukocytes to mediate such a response in recipient mice looks promising, and suggests a strategy that could be translated into patients.