Devil Facial Tumour Diseases (DFTD), threatening Tasmanian devils, consist of two distinct transmissible cancers, DFT1 and DFT2, with differing origins and geographic spread. We investigated the metabolic differences between DFT1 and DFT2, examining cell viability, metabolic outputs, and bulk gene expression. Using both DFT1 and DFT2 cell lines and biopsies, we found that glycolysis, oxidative phosphorylation, glutamate metabolism, and fatty acid synthesis are all essential for the survival of both tumour types. However, DFT2 exhibited higher rates of glycolysis and lactate generation compared to DFT1. This coincided with elevated ATP production, cholesterol biosynthesis, and ROS generation, as well as an increased reliance on fatty acid metabolism. Furthermore, DFT2 is less metabolically adaptable than DFT1, being unable to switch to oxidative phosphorylation as DFT1 can when required. These metabolic changes in DFT2, in conjunction with its higher growth rate, suggest a more aggressive cancer phenotype than DFT1. Our findings highlight distinct metabolic adaptations in DFT2 that may contribute to its competitive advantage.

Tritrichomonas foetus is a protozoan parasite responsible for bovine trichomonosis, a venereal disease that causes reproductive failure in cows while leaving bulls asymptomatic. Currently, no vaccine is available in Australia. This study aimed to develop and assess the safety, efficacy, and immunogenicity of a locally sourced T. foetus whole-cell killed vaccine in young bulls. The TfOz5 Queensland isolate was used as the vaccine strain, and the TfOz-N36 Northern Territory isolate served as the challenge strain. The heat-inactivated vaccine, adjuvanted with Montanide ISA 61 VG, was administered subcutaneously to 30 tropical composite T. foetus-naïve bulls in two doses (5 × 10⁷ cells/dose) one month apart. Control bulls (n = 30) received a mock formulation of adjuvant and phosphate-buffered saline. Bulls were challenged with live T. foetus cells directly into the prepuce at two and six weeks post-second vaccination with 1.37 × 10⁷ and 2.70 × 10⁷ cells, respectively. The vaccine was well tolerated causing only mild local reactions with no significant differences in weight or average daily gain between groups. Vaccinated bulls exhibited a significantly shorter infection duration (14 vs. 40 days, p = 0.0044) and lower parasite DNA burden compared to controls. Vaccination induced a strong systemic IgG response, whereas mucosal IgA responses remained low in both groups. These findings demonstrate that the Australian whole-cell killed T. foetus vaccine was well tolerated under the monitored study conditions and was effective in reducing infection duration and parasite DNA burden in young bulls.

Tritrichomonas foetus is a protozoan parasite that causes bovine trichomonosis (also referred to as trichomoniasis) resulting in substantial economic loss in extensive grazing systems. The parasite colonises the reproductive tracts of both male and female cattle, being asymptomatic in males but causing early reproductive failure in infected females. This systematic review aimed to examine research manuscripts describing the development of T. foetus vaccines, the strategies employed, and the immune response associated with T. foetus infection. A systematic review was conducted using indexed sources on Scopus, PubMed, Web of Science, and Embase to search for published vaccine development studies in English utilising either experimental or commercial T. foetus vaccines for bovine trichomonosis. Search terms (cattle, bull, heifer, vaccine, immune response, and Tritrichomonas foetus) were entered into the indexed sources and with no limit was set for the year of publication. Among 374 studies imported for screening, 96 were duplicates, and 255 were excluded for irrelevancy as these studies did not meet the inclusion criteria (report original data, vaccine tests in cattle, and used either commercial or experimental vaccines that incorporated antigens from T. foetus). A further five studies were excluded after full-text review as either the publication described a different target pathogen or the full text was not in English. Eighteen studies met the inclusion criteria and were subjected to data extraction using the Covidence platform. Studies included in the systematic review reported three vaccine strategies, including subunit, cell fraction, and whole-cell killed vaccines. This review considers the design, rationale, and results of each of the 18 studies to provide a comprehensive overview of the current knowledge and to inform future research agendas. While whole-cell killed vaccines are most prevalent, they have shown superior efficacy compared to subunit vaccines studied to date. One study using a purified fractions of T. foetus cell membranes as vaccine demonstrated higher efficacy and higher calving rates compared to the whole-cell killed vaccine. All of these methods require cell culture growth of T. foetus which can be challenging compared to the production of recombinant proteins. At this stage, no T. foetus recombinant antigens have been reported. Advances in understanding the parasite's genome, pathogenesis, host-parasite interactions, and host immune responses to T. foetus will provide opportunities for the development of novel vaccine strategies for bovine trichomonosis.

BackgroundBovine genital campylobacteriosis (BGC) is a globally important venereal disease of cattle caused by Campylobacter fetus subspecies venerealis. Diagnosis of BGC is highly challenging due to the lack of accurate diagnostic tests.MethodsTo characterise the biomarkers for C. fetus venerealis infection, a total of twelve cycling heifers were selected and categorised as vaccinated (n = 6) with Vibrovax® (Zoetis™) and unvaccinated (n = 6). All heifers were oestrous synchronised with a double dose of prostaglandin (PGF2α) 11 days apart and when in oestrous intravaginally challenged with 2.7 x 109 CFU live C. fetus venerealis. DNA extracted from vaginal mucus samples was screened using a C. fetus qPCR and 16S rRNA was characterised using Illumina sequencing (V5-V8 region). Relative abundances of serum proteins were calculated using sequential window acquisition of all theoretical fragment ion spectra coupled to tandem mass spectrometry (SWATH-MS) for all heifers at three timepoints: pre-challenge, post-challenge and post-recovery.ResultsIn 16S rRNA sequencing of vaginal mucus, Campylobacter spp. appeared two days following challenge in unvaccinated compared to 14 days in vaccinated animals, consistent with the qPCR results. Increased relative abundances of Firmicutes and Campylobacterota were identified after C. fetus venerealis challenge and were associated with C. fetus venerealis in vaccinated and unvaccinated heifers. Greater relative abundance of Streptococcus spp. was observed during oestrous rather than dioestrous. In both vaccinated and unvaccinated heifers, Acinetobacter spp. increased after challenge with higher abundance of Corynebacterium spp. in the vaccinated group. A total of 130 unique proteins were identified in SWATH analysis of the serum samples, and the number of differentially abundant proteins found was higher in the vaccinated group after recovery from infection compared to pre-and post-challenge (adjusted P < 0.05 and Log2FC > 0.2).ConclusionCoglutinin, clusterin, HP homologs, vitamin D binding protein and fetuin B were identified as potential biomarkers for C. fetus venerealis infection and need further study to validate their efficiency as immune biomarkers for BGC.

Reproductive diseases and illnesses pose significant challenges in cattle farming, affecting fertility, milk production, and overall herd health. In recent years, the integration of various omics approaches, including transcriptomics, proteomics, metagenomics, miRNAomics, and metabolomics, has revolutionized the study of these conditions. This systematic review summarised the findings from studies that investigated reproductive disease biomarkers in both male and female cattle. After extracting 6137 studies according to exclusion and inclusion criteria, a total of 60 studies were included in this review. All studies identified were associated with female cattle and none were related to reproductive diseases in bulls. The analysis highlights specific biomarkers, metabolic pathways, and microbial compositions associated with bovine reproductive disease conditions, providing valuable insights into the underlying molecular mechanisms of disease. Pro-inflammatory cytokines such as IL-1β, IL-8, IL-4, IL-6, TNFα and acute-phase response proteins such as SAA and HP have been identified as promising biomarkers for bovine reproductive diseases. However, further research is needed to validate these markers clinically and to explore potential strategies for improving cow reproductive health. The role of bulls as carriers of venereal diseases has been underestimated in the current literature and therefore needs more attention to understand their impact on infectious reproductive diseases of female cattle.

AbstractSince the emergence of a transmissible cancer, devil facial tumour disease (DFT1), in the 1980s, wild Tasmanian devil populations have been in decline. In 2016, a second, independently evolved transmissible cancer (DFT2) was discovered raising concerns for survival of the host species. Here, we applied experimental and modelling frameworks to examine competition dynamics between the two transmissible cancers in vitro. Using representative cell lines for DFT1 and DFT2, we have found that in monoculture, DFT2 grows twice as fast as DFT1 but reaches lower maximum cell densities. Using co‐cultures, we demonstrate that DFT2 outcompetes DFT1: the number of DFT1 cells decreasing over time, never reaching exponential growth. This phenomenon could not be replicated when cells were grown separated by a semi‐permeable membrane, consistent with exertion of mechanical stress on DFT1 cells by DFT2. A logistic model and a Lotka–Volterra competition model were used to interrogate monoculture and co‐culture growth curves, respectively, suggesting DFT2 is a better competitor than DFT1, but also showing that competition outcomes might depend on the initial number of cells, at least in the laboratory. We provide theories how the in vitro results could be translated to observations in the wild and propose that these results may indicate that although DFT2 is currently in a smaller geographic area than DFT1, it could have the potential to outcompete DFT1. Furthermore, we provide a framework for improving the parameterization of epidemiological models applied to these cancer lineages, which will inform future disease management.

Bovine babesiosis, caused by different Babesia spp. such as B. bovis, B. bigemina, B. divergens, and B. major, is a global disease that poses a serious threat to livestock production. Babesia bovis infections are associated with severe disease and increased mortality in adult cattle, making it the most virulent agent of bovine babesiosis. Babesia bovis parasites undergo asexual reproduction within bovine red blood cells, followed by sexual reproduction within their tick vectors, which transmit the parasite transovarially. Current control methods, including therapeutic drugs (i.e., imidocarb) have been found to lead to drug resistance. Moreover, changing environmental factors add complexity to efficient parasite control. Understanding the fundamental biology, host immune responses, and host-parasite interactions of Babesia parasites is critical for developing next-generation vaccines to control acute disease and parasite transmission. This systematic review analyzed available research papers on vaccine development and the associated immune responses to B. bovis. We compiled and consolidated the reported vaccine strategies, considering the study design and rationale of each study, to provide a systematic review of knowledge and insights for further research. Thirteen studies published since 2014 (inclusive) represented various vaccine strategies developed against B. bovis such as subunit, live attenuated, and viral vector vaccines. Such strategies incorporated B. bovis proteins or whole live parasites with the latter providing the most effective prophylaxis against bovine babesiosis. Incorporating novel research approaches, such as "omics" will enhance our understanding of parasite vulnerabilities.

Although the true prevalence of transmissible cancers is not known, these atypical malignancies are likely rare in the wild. The reasons behind this rarity are only partially understood, but the "Perfect Storm hypothesis" suggests that transmissible cancers are infrequent because a precise confluence of tumor and host traits is required for their emergence. This explanation is plausible as transmissible cancers, like all emerging pathogens, will need specific biotic and abiotic conditions to be able to not only emerge, but to spread to detectable levels. Because those conditions would be rarely met, transmissible cancers would rarely spread, and thus most of the time disappear, even though they would regularly appear. Thus, further research is needed to identify the most important factors that can facilitate or block the emergence of transmissible cancers and influence their evolution. Such investigations are particularly relevant given that human activities are increasingly encroaching into wild areas, altering ecosystems and their processes, which can influence the conditions needed for the emergence and spread of transmissible cell lines.

MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4+ T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.

Devil facial tumour disease (DFTD) is a transmissible cancer that has circulated in the Tasmanian devil population for >25 years. Like other contagious cancers in dogs and devils, the way DFTD escapes the immune response of its host is a central question to understanding this disease. DFTD has a low major histocompatibility complex class I (MHC-I) expression due to epigenetic modifications, preventing host immune recognition of mismatched MHC-I molecules by T cells. However, the total MHC-I loss should result in natural killer (NK) cell activation due to the ‘missing self’. Here, we have investigated the expression of the nonclassical MHC-I, Saha-UD as a potential regulatory or suppressive mechanism for DFTD. A monoclonal antibody was generated against the devil Saha-UD that binds recombinant Saha-UD by Western blot, with limited crossreactivity to the classical MHC-I, Saha-UC and nonclassical Saha-UK. Using this antibody, we confirmed the expression of Saha-UD in 13 DFTD tumours by immunohistochemistry (n = 15) and demonstrated that Saha-UD expression is heterogeneous, with 12 tumours showing intratumour heterogeneity. Immunohistochemical staining for the Saha-UD showed distinct patterns of expression when compared with classical MHC-I molecules. The nonclassical Saha-UD expression by DFTD tumours in vivo may be a mechanism for immunosuppression, and further work is ongoing to characterise its ligand on immune cells.

Contagious cancers are a rare pathogenic phenomenon in which cancer cells gain the ability to spread between genetically distinct hosts. Nine examples have been identified across marine bivalves, dogs and Tasmanian devils, but the Tasmanian devil is the only mammalian species known to have given rise to two distinct lineages of contagious cancer, termed Devil Facial Tumour 1 (DFT1) and 2 (DFT2). Remarkably, DFT1 and DFT2 arose independently from the same cell type, a Schwann cell, and while their ultra-structural features are highly similar they exhibit variation in their mutational signatures and infection dynamics. As such, DFT1 and DFT2 provide a unique framework for investigating how a common progenitor cell can give rise to distinct contagious cancers. Using a proteomics approach, we show that DFT1 and DFT2 are derived from Schwann cells in different differentiation states, with DFT2 carrying a molecular signature of a less well differentiated Schwann cell. Under inflammatory signals DFT1 and DFT2 have different gene expression profiles, most notably involving Schwann cell markers of differentiation, reflecting the influence of their distinct origins. Further, DFT2 cells express immune cell markers typically expressed during nerve repair, consistent with an ability to manipulate their extracellular environment, facilitating the cell's ability to transmit between individuals. The emergence of two contagious cancers in the Tasmanian devil suggests that the inherent plasticity of Schwann cells confers a vulnerability to the formation of contagious cancers.

Transmissible cancers are malignant cells that can spread between individuals of a population, akin to both a parasite and a mobile graft. The survival of the Tasmanian devil, the largest remaining marsupial carnivore, is threatened by the remarkable emergence of two independent lineages of transmissible cancer, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to major histocompatibility complex class I (MHC-I) molecules from Tasmanian devil cells and representative cell lines of each transmissible cancer. Here, we show that DFT1 + IFN-γ and DFT2 cell lines express a restricted repertoire of MHC-I allotypes compared with fibroblast cells, potentially reducing the breadth of peptide presentation. Comparison of the peptidomes from DFT1 + IFNγ, DFT2 and host fibroblast cells demonstrates a dominant motif, despite differences in MHC-I allotypes between the cell lines, with preference for a hydrophobic leucine residue at position 3 and position Ω of peptides. DFT1 and DFT2 both present peptides derived from neural proteins, which reflects a shared cellular origin that could be exploited for vaccine design. These results suggest that polymorphisms in MHC-I molecules between tumours and host can be 'hidden' by a common peptide motif, providing the potential for permissive passage of infectious cells and demonstrating complexity in mammalian histocompatibility barriers.

MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The transmissible devil facial tumour (DFT) cells that cause Tasmanian devil facial tumour disease (DFTD) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. MHC-II expression is crucial for CD4+ T cell activation and is primarily confined to haematopoietic antigen presenting cells. We discovered that the MHC-II transactivator, CIITA, can induce MHC-II expression in non-haematopoietic cells. Transcriptomic analysis of DFT cell lines revealed that CIITA can upregulate several genes of the MHC-I and MHC-II pathways, resulting in protein expression of MHC-I and MHC-II complexes. The induced expression of MHC-II in transmissible cancers signifies that CIITA can function in non-haematopoietic cancer cells and offer a novel strategy to enhance tumour recognition via MHC-II-restricted tumour antigen presentation.Non-haematopoietic devil facial tumour (DFT) cells do not typically express MHC-IICIITA regulates components of the MHC-I and MHC-II machinery in DFT cellsCIITA can induce MHC-I and MHC-II expression in DFT1 cellsSerum from devils with tumour regressions binds to DFT cells that express CIITAMHC-II expression in transmissible cancers has implications for anti-tumour immunity

Ecological and evolutionary concepts have been widely adopted to understand host-pathogen dynamics, and more recently, integrated into wildlife disease management. Cancer is a ubiquitous disease that affects most metazoan species; however, the role of oncogenic phenomena in eco-evolutionary processes and its implications for wildlife management and conservation remains undeveloped. Despite the pervasive nature of cancer across taxa, our ability to detect its occurrence, progression and prevalence in wildlife populations is constrained due to logistic and diagnostic limitations, which suggests that most cancers in the wild are unreported and understudied. Nevertheless, an increasing number of virus-associated and directly transmissible cancers in terrestrial and aquatic environments have been detected. Furthermore, anthropogenic activities and sudden environmental changes are increasingly associated with cancer incidence in wildlife. This highlights the need to upscale surveillance efforts, collection of critical data and developing novel approaches for studying the emergence and evolution of cancers in the wild. Here, we discuss the relevance of malignant cells as important agents of selection and offer a holistic framework to understand the interplay of ecological, epidemiological and evolutionary dynamics of cancer in wildlife. We use a directly transmissible cancer (devil facial tumour disease) as a model system to reveal the potential evolutionary dynamics and broader ecological effects of cancer epidemics in wildlife. We provide further examples of tumour-host interactions and trade-offs that may lead to changes in life histories, and epidemiological and population dynamics. Within this framework, we explore immunological strategies at the individual level as well as transgenerational adaptations at the population level. Then, we highlight the need to integrate multiple disciplines to undertake comparative cancer research at the human-domestic-wildlife interface and their environments. Finally, we suggest strategies for screening cancer incidence in wildlife and discuss how to integrate ecological and evolutionary concepts in the management of current and future cancer epizootics.

Transmissible cancers are spread via the passage of malignant cells. The survival of the Tasmanian devil, the largest marsupial carnivore, is threatened by two independent transmissible cancers, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a peptide vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to Major Histocompatibility Complex class I molecules from the Tasmanian devil and its transmissible tumours. Comparison of the peptidomes from DFT1+IFNγ, DFT2 and host fibroblast cells demonstrates a shared motif, despite differences in MHC-I allotypes between the cell lines. Importantly, DFT1+IFNγ and DFT2 share the presentation of peptides derived from neural proteins, reflecting a common cellular origin that should be exploited for vaccine design. These results suggest that some polymorphisms between tumours and host are ‘hidden’ by a common peptide motif, providing the potential for permissive passage of infectious cells.

Modern conservation science frequently relies on genetic tools to manage imperiled populations threatened by processes such as habitat fragmentation and infectious diseases. Translocation of individuals to restore genetic diversity (genetic rescue) is increasingly used to manage vulnerable populations (Whiteley et al. 2015), but it can swamp local adaptations and lead to outbreeding depression (Frankham et al. 2011). Thus, genetic management is context dependent and needs evaluation across multiple generations (Fitzpatrick et al. 2020). Genomic studies can help evaluate the extent to which populations are locally adapted to assess the costs and benefits of translocations. Predicting the long-term fitness effects of genetic interventions and their evolutionary consequences is a vital step in managing dwindling populations threatened by emerging infectious diseases. Multicellular organisms have a long evolutionary history with oncogenic phenomena. While some cancer-protection adaptations are very old and phylogenetically well conserved, such as cancer-suppression mechanisms (Nunney 2013), others are species specific and shaped by ecological processes and life-history traits (Ujvari et al. 2016). An increasing number of infectious cancers, virus associated and directly transmissible, are occurring in terrestrial and aquatic environments (Hamede et al. 2020). Thus, cancer is nowadays regarded as a disease of conservation concern (McAloose & Newton 2009), particularly for threatened wildlife (Hamede at al. 2020). We considered the Tasmanian devil (Sarcophilus harrisii) and its transmissible cancers as a model to examine the integration of knowledge of host-pathogen evolutionary interactions with wildlife disease management. Devils have been afflicted by a transmissible cancer (devil facial tumor disease [DFTD]) for at least 24 years (Hawkins et al. 2006). The DFTD epidemic has caused significant population declines (McCallum et al. 2009) and led to the species' listing as endangered (Hawkins et al. 2009). In 2014 another, independently evolved, transmissible cancer (devil facial tumor 2 [DFT2]) was discovered in southeastern Tasmania (Pye et al. 2016b). Translocations of captive or free-range devils sourced from insurance populations with the aim of genetic rescue (Grueber et al. 2019) are being tested, as are field immunizations aimed at stimulating an adaptive immune response (Pye et al. 2018). However, the epidemiological and evolutionary consequences of introducing naïve individuals from insurance populations into diseased populations have not been evaluated comprehensively, thus, current management is unlikely to prevent transmission. Darwinian principles, host-pathogen coevolutionary theory, and the growing literature on ecological and evolutionary principles in oncology (Korolev et al. 2014) suggest that silver bullets are unlikely to result in disease eradication. We considered evolutionary biology and ecology of host-pathogen interactions to highlight why the role of natural selection in host adaptations to cancer should be considered in the management of this species and other epizootics. Early in the epizootic, DFTD caused localized population declines of up to 90% (McCallum et al. 2009). Once tumors were detected, they were universally fatal. After 10 years, DFTD had reduced effects at the epidemic frontline (Hamede et al. 2012). Devils from populations in northwestern Tasmania mounted immune responses to DFTD, concomitant with natural tumor regressions and recovery after infection (Pye et al. 2016a) (Fig 1). Devils with regressed tumors differed genetically from those with nonregressed tumors (Margres et al. 2018a), and tumor regressions appear to be affected by upregulation of putative tumor suppressor RASL11a, a gene not expressed in human cancers (Margres et al. 2020). Allele frequencies in genomic regions associated with immune function and cancer changed significantly 4-6 generations after disease arrival (Epstein et al. 2016). These changes occurred in 3 geographically separated populations and concurred with patterns of cessation of population decline at these sites. Moreover, a small number of loci explains significant variation in case control (diseased vs. never diseased devils) and survival of infected females (Margres et al. 2018b). These results provide evidence of rapid evolutionary responses, likely resulting from extreme selection imposed by DFTD, and demonstrate that devils have sufficient genetic variation to respond and adapt to the DFTD epidemic, despite limited genetic diversity (Bruniche-Olsen et al. 2014). Evidence of devil evolutionary responses to DFTD in geographically widespread locations (east, north, and northwest) warrants a conservation strategy that facilitates these beneficial adaptations. However, current plans include translocating individuals sourced from captive, DFTD-naïve populations into wild populations that have undergone generations of selection for resistance or tolerance. Increasing the number of susceptible individuals in diseased devil populations is likely to fuel the epidemic by increasing infection rates and potentially diluting or delaying selective processes. The adaptive response of the devil to DFTD involves interacting mechanisms and genes; thus, we suggest captive-breeding programs incorporate wild-sourced devils with genotypes that exhibit resistance or tolerance to DFTD. Future studies should identify evolutionary trade-offs associated with resistance or tolerance to DFTD and their potential fitness effects. To acquire herd immunity, over two-thirds of a population would need to be vaccinated, given the estimated reproductive rate of DFTD (McCallum et al. 2009). Offspring of vaccinated devils would be susceptible and facilitate DFTD transmission. Although the development of a vaccine is laudable, with potential future benefits for management (Patchett & Woods 2019), premature vaccination in the wild could have detrimental effects, particularly if the vaccine cannot provide life-time immunity in 1 shot. Vaccines that let the host survive and do not entirely prevent infection and spread can create ecological and epidemiological conditions that facilitate evolution and persistence of more virulent pathogen strains (e.g., Gandon et al. 2001; Mackinnon et al. 2008). Natural selection should remove highly lethal pathogens if the death rate of hosts significantly reduces transmission. However, if vaccinations prolong host survival without precluding transmission, pathogen replication is favored (Read et al. 2015), which may result in higher prevalence and favor persistence of tumor strains that might not be viable under natural selection. Therefore, before widespread vaccination in the wild, experiments to prove the prophylactic effect of vaccines and modeling of epidemic outcomes should be conducted. Coexistence of devils and DFTD is the most likely long-term enzootic outcome predicted by epidemiological models based solely on ecological processes (i.e., no explicit genetic component) (Wells et al. 2019). Incorporating evolutionary change in epidemiological models will likely strengthen the likelihood of coexistence of devils and DFTD without management. However, incorporating loss of genetic diversity may decrease the likelihood of coexistence without further intervention. One of the greatest difficulties, characterized by emerging infectious diseases and anthropogenic disturbance, is to determine whether human intervention should be undertaken and whether its benefits outweigh the benefits of facilitating recovery through natural selection. Interventions that enhance the prospects of devil recovery via local adaptation should be prioritized, but relying solely on evolution of natural adaptations to protect the species is risky, particularly considering that the evolutionary interactions and epidemiological outcomes between DFTD and DFT2 have not been evaluated fully. The emergent DFT2 warrants further caution because observed adaptations to DFTD may not be relevant to DFT2. The cumulative effects of 2 transmissible cancers and other threats need to be considered to balance the fitness effects of locally adapted populations to transmissible tumors and the loss of genetic diversity. There is a fundamental conundrum between maximizing genetic diversity (genetic rescue) and allowing natural selection to progress (evolutionary rescue). In the case of devils, where much empirical evidence shows rapid evolution in response to DFTD in the wild and potential functional genetic changes have been identified, we argue that management of adaptive genetic diversity should be prioritized. Captive-breeding programs to maintain genetic diversity are fundamental to protecting vulnerable populations. The case of Tasmanian devils and their cancer epizootics illustrates the importance of developing cross-disciplinary approaches capable of timely assessments of the ecoevolutionary processes between hosts and pathogens and their consideration for management. Therefore, we encourage managers and researchers to engage in a scientific debate that integrates new knowledge and offers novel methods to assess the effects of management on evolutionary and epidemiological dynamics in the devil-DFTD-DFT2 system. Evolutionary responses to pathogens with high mortality are not restricted to devils and DFTD. There is evidence of rapid evolutionary change in other host populations subject to emerging wildlife diseases (e.g., frogs in Central America exposed to chytrid fungus [Voyles et al. 2018]). Principles of evolutionary versus genetic rescue are also relevant in other contexts, such as rapid environmental change (e.g., climate-adjusted provenancing), and have direct implications for biodiversity conservation and ecological restoration (Prober et al. 2015). Genomic research is fine tuning and improving the capacity to understand the genetic basis of adaptation. Balancing the priorities of genetic rescue and evolutionary rescue is a critical task for conservation. Modern genomic methods, as exemplified by work on Tasmanian devils and DFTD, provide new tools for integrated management of populations threatened by diseases. For researchers and managers, the fundamental principle should be as espoused in the Hippocratic Oath, first, do no harm. This work was supported by the Australian Research Council (DE 170101116; LP 170101105), the National Institutes of Health—USA (NIH R01-GM12563), International Associated Laboratory Project France/Australia, and Agence Nationale de la Recherche (ANR Blanc Project TRANSCAN).

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

Emerging infectious diseases are rising globally and understanding host-pathogen interactions during the initial stages of disease emergence is essential for assessing potential evolutionary dynamics and designing novel management strategies. Tasmanian devils (Sarcophilus harrisii) are endangered due to a transmissible cancer-devil facial tumour disease (DFTD)-that since its emergence in the 1990s, has affected most populations throughout Tasmania. Recent studies suggest that devils are adapting to the DFTD epidemic and that disease-induced extinction is unlikely. However, in 2014, a second and independently evolved transmissible cancer-devil facial tumour 2 (DFT2)-was discovered at the d'Entrecasteaux peninsula, in south-east Tasmania, suggesting that the species is prone to transmissible cancers. To date, there is little information about the distribution, epidemiology and effects of DFT2 and its interaction with DFTD. Here, we use data from monitoring surveys and roadkills found within and adjacent to the d'Entrecasteaux peninsula to determine the distribution of both cancers and to compare their epidemiological patterns. Since 2012, a total of 51 DFTD tumours have been confirmed among 26 individuals inside the peninsula and its surroundings, while 40 DFT2 tumours have been confirmed among 23 individuals, and two individuals co-infected with both tumours. All devils with DFT2 were found within the d'Entrecasteaux peninsula, suggesting that this new transmissible cancer is geographically confined to this area. We found significant differences in tumour bodily location in DFTD and DFT2, with non-facial tumours more commonly found in DFT2. There was a significant sex bias in DFT2, with most cases reported in males, suggesting that since DFT2 originated from a male host, females might be less susceptible to this cancer. We discuss the implications of our results for understanding the epidemiological and evolutionary interactions of these two contemporary transmissible cancers and evaluating the effectiveness of potential management strategies.

The Tasmanian devil is the only mammalian species to harbour two independent lineages of contagious cancer. Devil facial tumour 1 (DFT1) emerged in the 1990s and has caused significant population declines. Devil facial tumour 2 (DFT2) was identified in 2014, and evidence indicates that this new tumour has emerged independently of DFT1. While DFT1 is widespread across Tasmania, DFT2 is currently found only on the Channel Peninsula in south east Tasmania. Allograft transmission of cancer cells should be prevented by major histocompatibility complex (MHC) molecules. DFT1 avoids immune detection by downregulating MHC class I expression, which can be reversed by treatment with interferon-gamma (IFNγ), while DFT2 currently circulates in hosts with a similar MHC class I genotype to the tumour. Wild Tasmanian devil numbers have not recovered from the emergence of DFT1, and it is feared that widespread transmission of DFT2 will be devastating to the remaining wild population. A preventative solution for the management of the disease is needed. Here, we review the current research on immune responses to devil facial tumours and vaccine strategies against DFT1 and outline our plans moving forward to develop a specific, effective vaccine to support the wild Tasmanian devil population against the threat of these two transmissible tumours.