Immunization Strategies Producing a Humoral IgG Immune Response against Devil Facial Tumor Disease in the Majority of Tasmanian Devils Destined for Wild Release

Abstract

Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government’s Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (N = 19 and N = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol®) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild.

A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

“…Previous DFT vaccine efforts have used killed DFT cells with adjuvants 62, 63 . A similar approach to treat gliomas in dogs reported that tumor-lysate with CD200 peptides nearly doubled progression-free survival compared to tumor lysate alone 64 .…”

Conserving adaptive potential: lessons from Tasmanian devils and their transmissible cancer

“…Experimentally treating devils with radiation-killed DFTD cells can produce a detectable immune response, which in some cases led to tumor regression in captive animals (Tovar et al 2017). Pye et al (2018) found that devils treated with DFTD cells manipulated to produce MHC class I antigens induce an antibody response in devils released into the wild. Yet despite this progress, it is not yet known whether immunization may be protective against DFTD infection in the field.…”

Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes

“…MHC-I down-regulation in these tumours is due to epigenetic mechanisms and can be reversed by treatment with the pro-inflammatory cytokine interferon gamma (IFNg) (18). However, rare instances of spontaneous DFT1 tumour regression have been described and vaccination and immunotherapy of devils with live MHC-I positive DFT1 cells demonstrate that devils can mount an effective immune response against the disease in some instances (19)(20)(21). We have 5 recently shown that in contrast to DFT1, DFT2 cells express MHC-I molecules, but the expressed alleles are similar between hosts and tumours in the samples analysed (1).…”

“…A unique opportunity exists to limit the spread of this 'new' tumour, before it causes the level of infection of DFT1. MHC + -DFT1 cells have become the focus of intense research to determine if they are allogenic to host devils and have potential as a whole cell vaccine against DFT1 (19,21). Preliminary results have shown that MHC + -DFT1 cells can stimulate a protective immune response in host devils but the mechanisms are not understood and the results are variable among host devils.…”