Devil Dispatch: MHC the Key to Contagious Cancer Vaccine?

28 April 2013 by Anne-Marie Hodge, posted in Uncategorized

The contagious cancer currently ripping through Tasmanian devil (Sarcophilus harrisii) populations has captivated public attention and imagination. The reasons for this are understandable. First, in a world where cancer kills 7.6 million people every year, just the idea of tumor cells that can be passed along between individuals like a cold or flu is a horrific notion to contemplate—a concept straight out of a cheap thriller novel. Also, the irascible Tasmanian devil has a sort of anti-charisma—fearsome temper, frightening countenance (even before infection with deadly facial tumors), and a name with sinister connotations . . . how can we help but love it?

Tasmanian devil suffering from DFTD

About a year and a half ago, I wrote about devil facial tumor disease (DFTD), the transmissible cancer that is pushing the Tasmanian devil closer and closer to the edge of extinction (see that post for a detailed discussion about the biology of contagious cancer). In the mean time, scientists have continued to press onward in pursuit of a way to stop DFTD’s spread and attempt to prevent the extinction of this unique and endangered marsupial. Last month, a fascinating and promising new discovery about DFTD was published in the Proceedings of the National Academy of Sciences (Siddle et al. 2013), and it looks as though there may actually be a light at the end of the tunnel for those who have worked so hard to understand and beat the disease—and for the devils themselves, of course.

As you might remember from my earlier post, there are two known transmissible cancers, DFTD and canine transmissible venereal tumor (CTVT), a sexually transmitted strain of cancer found in dogs and a few wild canids. Although DFTD is invariably fatal, CTVT rarely kills its hosts. Why? This question was a key starting point for Siddle and colleagues as they embarked on this new study. The researchers reasoned that the vast difference in mortality rate between the two diseases indicates that there must be something different about how the DFTD cells and CTVT cells interact with host immune systems.

Before we dive farther into the study, let’s have a very basic refresher course on mammalian immune responses. In order to recognize non-self cells (ie, those resulting from an infection or another foreign source), the immune system’s T-cells rely upon signals from the major histocompatibility complex (MHC) molecules that are displayed on the outside of the cell walls. These are the signals that tell the animals’ body, “this cell is mine, let it go about its business in peace,” or “Invader! Attack!” The expression of MHC molecules is controlled by a dizzying array of transcription factors, cytokines, DNA promoter elements, and epigenetic changes that occur over the course an organism’s development. Through their control of MHC activity, these factors influence the ability of the immune system to recognize “non-self” cells that need to be isolated and destroyed.

The progression of CTVT infection is interesting from an MHC perspective. For the first couple of months after an animal is infected, its CTVT cells don’t express MHC—the tumors fly under the immunological radar. Starting three to nine months after infection, however, the cells finally begin to express the MHC signals, and this allows lymphocytes to recognize the tumor cells as a problem and go in for the attack (Pérez et al. 1998; Hsiao et al. 2008). This is likely why CTVT is nowhere near as fatal as DFTD.

Now, it had long puzzled researchers that DFTD cells can be grafted between individuals with no rejection effect whatsoever—the animal’s body cannot tell that the tumor came from another devil. This is not due to extreme genetic similarity between devils—they have sufficient genetic variation that their immune systems should recognize a cell from another individual. (Sidebar: One often-told story is that cheetahs are famously so genetically homogenous that captive animals fail to reject skin grafts from other cheetahs, even without anti-rejection drugs . . . but newer research on wild cheetahs has shown that although there is indeed very low MHC variation, they are not as immunologically vulnerable as once thought).

So, back to devils. We have a transmissible cancer with a 100% mortality rate, and with cells that can be shuffled around between individuals with no alarm from the immune system…it seems clear that we needed a better understanding of exactly what is going on with the MHC molecules on DFTD cells.

Siddle and colleagues proceeded to isolate three cell lines from DFTD tumors, using a devil fibroblast cell line as a control. They cultured these cell lines in the lab, and conducted a series of tests to look at the activity of genes regulating MHC expression. They also checked to see if the DFTD cells exhibit structural abnormalities that could affect MHC recognition.

Siddle et al. (2013) show that DFTD cells do not express MHC molecules on their cell surfaces—in other words, they act like Trojan horses for the cancer, with no signal to the immune system that the tumor cells are a cause for concern. It turns out that DTFD cells down-regulated genes that are required for antigen processing, ultimately leading to a lack of MHC expression on the outside of the tumor cells. Without that signal from the MHC molecules, the immune system is oblivious to this sinister presence, and the cancer proliferates until it has killed the animal—explaining why this disease has a 100% mortality rate. The loss of gene expression was due to epigenetic modifications of the regulatory units, not to structural abnormalities of the tumor cells themselves.

Yes, this is quite upsetting news for a devil.

The discoveries didn’t stop there. Siddle’s group also tried treating the tumor cells with two substances: an antifungal drug called Trichostatin A, which is known to affect the activity of genes involved in MHC regulation, and a cytokine called interferon gamma, which had previously been shown to limit the growth of CTVT tumors. Both treatments resulted in a reactivating of the MHC gene activity, allowing the DFTD cells to be labeled as cause for alarm.

The upshot of this is intriguing: the authors suggest that the new discovery could yield a vaccine against DFTD. If devils can be inoculated with DFTD cells that have their MHC machinery reactivated, we may have finally found a way to allow the devils’ immune systems to fight off the tumor cells.

There is still much work to be done before this solution becomes a reality, of course. There are other ways the DFTD cells try to evade the immune system, and further research is needed to determine the best way way to strip the tumors of as many defenses as possible. Still, this is an exciting advance. For a species as close to the extinction abyss as the Tasmanian devil, good news can be scarce, and this study is definitely a cause for hope.

 

 

ResearchBlogging.org

 

 

 

Hsaio YW, et al. (2008). Interactions of hos IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression during tumor spontaneous regression. Cancer Immunology, Immunotherapy, 57 (7), 1091-1104.

Pérez J, Day MJ, Mozoz E. (1998). Immunohistochemical study of hte local inflammatory infiltrate in spontaneous canine transmissible venereal tumour at different stages of growth. Veterinary Immunology and Immunopathology, 64 (2), 133-147.

Siddle HV, Kreiss A, Tovar C, Yuen CK, Cheng Y, Belov K, Swift K, Pearse AM, Hamede R, Jones ME, Skjødt K, Woods GM, & Kaufman J. (2013). Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proceedings of the National Academy of Sciences of the United States of America, 110 (13), 5103-8 PMID: 23479617

 

All images sourced from Wikimedia Commons.


4 Responses to “Devil Dispatch: MHC the Key to Contagious Cancer Vaccine?”

  1. Khalil A. Cassimally Reply | Permalink

    That first picture of the Tassie Devil makes me real sad but the research detailed here is promising. I do wonder why it took this long for scientists to realise that the evading mechanism was because of the non-expression of MHC though.

    More importantly, considering the that devil's numbers is constantly shrinking, the need for a cure/vaccine is very important. I do hope that we can find something for them before they reach critically low numbers.

  2. Peter Vásárhelyi Reply | Permalink

    while i don't know much Hard Science, i do remember a show on either Nat Ge0, OR Disc. channel, that addressed the issue regarding the 'Devil's being on the Verge of Extinction .. .. i do seem to recall, from said show as well, that they'd managed to capture a Live Specimen, one WITHOUT the TFDT, and that they were looking into finding a Mate for it .. .. alas, i think it's a year or 2 ago i saw that show
    many things may have happened since then, tho', and this wellwritten article, is
    definitely newer .. .. while i'm as sorry for the li'l Bugger's, as everyone else with a
    Heart for Animal's, it did leave me kinda heartened to read this Article

    Peter

    p.s. thx to Miss/Mrs. Hodge for posting it :)

  3. Chris Noble Reply | Permalink

    Very nicely written article, however just one thing I don't understand.

    You say that treating the tumor cells with Trichostatin or interferon gamma, resulted in a reactivating of the MHC gene activity.

    It's not clear to me however why inoculating the devils with treated DFTD cells is the answer.

    1. Why not simply inject devils suffering from DFTD with trichstatin or interferon?

    2. How does inoculating with treated DFTD cells has any effect on stopping a subsequent DFTD infection since the new DFTD presumably won't express MHC.

  4. Rebekah Reply | Permalink

    Really enjoyed reading; you made this understandable for the non-science majors, like myself. :]
    Also, I had not known of "research blogging" until seeing this (saw it on Reddit). Awesome.

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