Immunology of a Transmissible Cancer Spreading among Tasmanian Devils Gregory M. Woods, Lauren J. Howson, Gabriella K. Brown, Cesar Tovar, Alexandre Kreiss, Lynn M. Corcoran and A. This information is current as Bruce Lyons of September 29, 2021. J Immunol 2015; 195:23-29; ; doi: 10.4049/jimmunol.1500131 http://www.jimmunol.org/content/195/1/23 Downloaded from References This article cites 62 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/195/1/23.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Immunology of a Transmissible Cancer Spreading among Tasmanian Devils Gregory M. Woods,*,† Lauren J. Howson,*,1 Gabriella K. Brown,*,2 Cesar Tovar,* Alexandre Kreiss,* Lynn M. Corcoran,‡ and A. Bruce Lyons† Devil facial tumor disease (DFTD) is a transmissible Understanding the immunology and immune escape mech- cancer that has killed most of the Tasmanian devil (Sar- anisms of this cancer has implications for tumor transmissi- cophilus harrissii) population. Since the first case bility and potential relevance for human cancers. appeared in the mid-1990s, it has spread relentlessly In the mid-1990s in the far northeast corner of Tasmania, across the Tasmanian devil’s geographic range. As Tas- the island state to the south of mainland Australia (Fig. 1A), manian devils only exist in Tasmania, Australia, DFTD a single Schwann cell from a female Tasmanian devil (Sar- has the potential to cause extinction of this species. The cophilus harrissii) developed into a cancer (5, 6). It is still Downloaded from origin of DFTD was a Schwann cell from a female growing today. This is because devils bite each other, facili- devil. The disease is transmitted when devils bite each tating continuous transmission of the cancer cells (7). Because the cancer occurs in the facial region, it was designated as other around the facial areas, a behavior synonymous , with this species. Every devil that is ‘infected’ with DFTD (8). This cancer is always fatal. In 20 y DFTD has spread across most of Tasmania (Fig. 1B–D), causing a cata- DFTD dies from the cancer. Once the DFTD cells http://www.jimmunol.org/ strophic crash in devil numbers (9). The decline is so severe have been transmitted, they appear to develop into that the devil is listed as endangered at international (Inter- a cancer without inducing an immune response. The national Union for Conservation of Nature “Red List of Threat- DFTD cancer cells avoid allogeneic recognition be- ened Species”), national, and state levels. cause they do not express MHC class I molecules on DFTD is one of only two currently known transmissible the cell surface. A reduced genetic diversity and the tumors. The other is canine transmissible venereal tumor production of immunosuppressive cytokines may also (CTVT). For .10,000 y, and usually during coitus, these contribute. The Journal of Immunology, 2015, 195: tumor cells have been transmitted between dogs (10). CTVT 23–29. does not metastasize and does not usually cause the death of by guest on September 29, 2021 the host (11). There are many excellent articles on CTVT (12–14) and reviews comparing CTVT and DFTD (15, 16). ransmissible cancers are exceedingly rare, as allorecog- This review concentrates on DFTD. nition of tumor cells should be the final barrier should T tumor cell transfer occur (1). A number of obligatory events are required for any cancer to be transmissible. The The Tasmanian devil and DFTD primary “index” tumor must occur in an accessible site, a Tasmanian devils are the world’s largest marsupial carnivore mode of transmission is essential, the tumor cells must avoid and exist only in Tasmania. They are generally nocturnal allorecognition, and they require the capacity for infinite scavengers that feed on carrion, but sometimes hunt for small growth. In combination, these simultaneous requirements mammals and birds (7). They usually have black fur with make the development of transmissible tumors extremely distinctive white markings on the rump and chest (Fig. 2A) unlikely. Examples in humans are limited, but include and weigh between 4.5 and 13 kg (7). Devils have extremely maternal–fetal transfer of melanoma in utero (2), as well as powerful jaws and teeth that enable them to completely de- those resulting from a medical procedure such as trans- vour their prey. Since the extinction of the Tasmanian tiger plantation where the recipient is immunosuppressed (3) or (Thylacinus cynocephalus), the Tasmanian devil is now the closely related to the donor (4). In human cases, transmission principal native carnivore in Tasmania (7). It therefore has to tertiary individuals has not been documented. Devil facial a vital role in the ecosystem. tumor disease (DFTD) is a current example of a naturally DFTD usually presents as large, solid, soft tissue masses with occurring transmissible cancer that meets the above criteria. flattened, centrally ulcerated, and exudative surfaces (Fig. 2B). *Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania Address correspondence and reprint requests to Prof. Gregory M. Woods, Menzies 7000, Australia; †School of Medicine, University of Tasmania, Hobart, Tasmania 7001, Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, Australia; and ‡Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria TAS 7000, Australia. E-mail address: [email protected] 3052, Australia Abbreviations used in this article: CTVT, canine transmissible venereal tumor; DFTD, 1 Current address: University of Oxford, Oxford, U.K. devil facial tumor disease; b2m, b2-microglobulin; MHC-I, MHC class I; MHC-II, MHC class II. 2Current address: Department of Health and Human Services, State Government of Tasmania, Hobart, TAS, Australia. Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Received for publication January 22, 2015. Accepted for publication April 29, 2015. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500131 24 BRIEF REVIEWS: IMMUNOLOGY OF TRANSMISSIBLE CANCER IN TASMANIAN DEVILS Downloaded from http://www.jimmunol.org/ FIGURE 1. Tasmania and the spread of DFTD. (A) Tasmanian devils are endemic to Tasmania. (B) Until the emergence of DFTD in the northeast of the state in 1996, Tasmanian devils were common throughout the island. The cancer is spreading like a contagious disease. (C) and (D) show the advance of the disease front (red shadow) in the last 10 y and the confirmed locations of DFTD (black stars). The disease currently affects .75% of the devils. It is commonly found in the oral, facial, or neck region or genotype are consistent between DFTD tumors and distinct inside the mouth. Necrosis, ulceration, exudation, and bac- from those of their hosts and supports the transmissible na- terial contamination are frequent. It often metastasizes to re- ture of the tumor. gional lymph nodes, lungs, and spleen (17). by guest on September 29, 2021 Histologically, the cancer cells in DFTD appear as pleo- DFTD transmission and immunology of Tasmanian devils morphic round cells with a high nuclear to cytoplasmic ratio, Devils bite each other on the face and neck, and the penetrating fibrillar, eosinophilic cytoplasm, and often indistinct cell bor- bites cause substantial wounds (22). The transfer of DFTD ders (Fig. 2C). DFTD cancers are well vascularized and display cells occurs when diseased devils bite healthy devils or when high mitotic indices. Lymphoid cell infiltration is usually poor healthy devils bite diseased devils (23). Males and females are (17). Transcriptome and miRNAome studies formally identified equally susceptible to DFTD. There is no evidence for vertical a Schwann cell origin for DFTD (6). Expression of periaxin, a transmission, as anecdotal reports indicate that DFTD dis- myelin protein, has proven to be a reliable diagnostic marker eased mothers do not transfer the cancer to their offspring. for DFTD (Fig. 2D) (18). Transmission occurs only between devils that display biting The most unusual characteristic of DFTD is its transmissible behaviors (24). nature. Early epidemiological observations suggested that The biting accounts for the transmission, but to become DFTD is transmissible, as the disease spread geographically established the “transplanted” cancer cells must avoid allo- over time (Fig. 1B–D), but the infectious agent was unknown geneic recognition. But how does this occur? One possibility (7). That the cancer cells themselves are the infectious agent is that devils have a compromised or rudimentary immune was confirmed by independent studies. The original sugges- system. Studies on a range of marsupials have provided evi- tion was based on chromosomal analysis, as different DFTD dence suggesting that they have an immune system that is less tumor isolates shared similar complex chromosomal rear- effective than that of placentals. This was originally based on rangements. One diseased devil had a pericentric inversion of the slower immune response of marsupials compared with chromosome 5 in its constitutional karyotype, but this in- placentals (25). A weak secondary response often follows the version was not observed in chromosome 5 of the tumor it prolonged primary response (26).