Transferable anticancer innate immunity in spontaneous regression/complete resistance mice
Transferable anticancer innate immunity in spontaneous regression/complete resistance mice
Amy M. Hicks, Gregory Riedlinger, Mark C. Willingham, Martha A. Alexander-Miller, C. Von Kap-Herr, Mark J. Pettenati, Anne M. Sanders, Holly M. Weir, Wei Du, Joseph Kim, Andrew J. G. Simpson, Lloyd J. Old, and Zheng Cui
Full Text Article: http://www.pnas.org/cgi/content/full/103/20/7753
This paper explored the properties and mechanisms behind the cancer immunity of spontaneous regression/complete resistance (SR/CR) mice, and its implications for the treatment of cancer. Spontaneous regression/complete resistance (SR/CR) mice have the ability to resist very high doses of cancer cells that are lethal to wild type (WT) mice even at low doses. The researchers found that this remarkable ability is mediated by the rapid infiltration of leukocytes, involving natural killer cells, macrophages, and neutrophils, which then triggers rapid cytolysis. These cell types from SR/CR mice also have the ability to independently kill cancerous cells in vitro. Remarkably, this resistance was also completely transferable to wild type mice through SR/CR splenocytes, bone marrow cells, or enriched peritoneal macrophages, either for prevention against future cancer or eradication of established malignancy.
The researchers found that the primary immune response was innate, (i.e. present without prior cancer exposure), but also found signs of adaptive immune responses, as the elimination of cancer cells was faster upon further exposures. Mice started out as spontaneous regression phenotypes, but after further exposure were entirely immune. In addition, they found the method involved the formation of rosettes between leukocytes and cancer cells that enable cytolysis of the cancerous cells. Interestingly, each individual type of leukocyte was able to kill cancer cells alone, without the other two types present. The researchers also developed an in vitro cancer-killing assay to identify SR/CR mice without needing to challenge them directly with cancer cells.
Next, the ability of transferred leukocytes to kill established tumors in wild-type mice was established. With injections of SR/CR leukocytes (4*10^8) from spleens and bone marrow, many solid tumors regressed completely or partially regressed and stabilized. In addition, the fully regressed mice were cancer-free at least until publication, more than 10 months after the experiment. This conferred immunity also worked in the absence of the adaptive immune system both in transferred leukocytes (no T and B cells) and in the recipient mice. Finally, Wild Type mice, when injected with the SR/CR leukocytes, stayed immune to large doses of cancerous cells even up to 12 months after transfer, and to multiple doses.
The most pressing need for future research is in determining the exact mechanism of the innate cancer immune response, as well as characterizing its behavior, if present, in humans. Determining the nature of the genetic change in SR/CR mice would open the door for finding other similar mutations, as well as improve the chances of finding such a mutation in human immune cells. Also, finding such immunity in human cells would open the possibility for using such immune cells as a cancer treatment.
These results could have a tremendous impact upon cancer treatment in the near future. If these properties and abilities are present in Human cells, then it could be possible to cure and prevent many varied types of cancer through simple immune cell transfusions. However, as the exact mechanism is not known, and the frequency of such natural immunity is rare in mice, it may be difficult at best to begin such treatments in the near future. Despite these shortcomings, this research shows great promise toward finding a cure for cancer.
6 comments:
Were the scientists able to isolate the SR/CR gene? If the SR/CR gene can't be found in humans, do you think transforming human cells to express that phenotype would be plausible?
Very interesting. So the authors were able to transfer immunity from these resistant sites to wild type mice with other cancers. However, their method is not very exact. For example, they transferred T and B cell depleted lymphocytes from the resistant mice to the wild type recipient mice, but they concede that the depleted lymphocytes are not really depleted and had <1% T and B cells. Is it possible that these residual cells could be the cause of the cancer killing and not the SR/CR leukocytes?
To answer your questions:
Elise: They were not able to isolate the SR/CR gene, and without this it could be very difficult, if possible, to get human cells to express such a phenotype.
Lizhi Cao: They also tried isolating each type of leukocyte in their in vitro cancer-killing assay, and each kind was able to effectively kill cancerous cells on their own. However, they do acknowledge that there is a component of the adaptive immune response, and so the T and B cells likely do play an important role in long-term immunity.
It doesn't seem farfetched that an anti-cancer immunity would be present within the human gene pool. There are tales of people who smoke packs of cigarettes until old age and never suffer from mouth/lung cancer. Has the group made any plans toward studying anti-cancer immunity in humans?
Wow, it is really neat that the ability to resist very high doses of cancer cells exhibited by these SR/CR mice can be completely transferred to wild type mice. Did the paper describe how the in vitro cancer-killing assay to identify SR/CR mice works? Could a variant of this assay be used to identify similar properties or abilities in humans?
To answer your questions:
William: The researchers indicated this was an important point of further research, but did not indicate whether they planned to do research into human immunity.
Achung: The in vitro killing assay was described in detail in another paper and primarily consisted of a local challenge with the cancer cells, then extraction of the leukocytes and cancer, and staining with Trypan Blue to determine live vs. dead.
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