The Tasmanian devil (Sarcophilus harrisii) is threatened by Devil Facial Tumour Disease (DFTD), comprising two transmissible cancers of Schwann cell origin (DFT1 and DFT2). The development of effective prophylactic vaccines against DFTD has been restricted by an incomplete understanding of how allogeneic DFT1 and DFT2 cells maintain immune evasion upon activation of tumour-specific immune responses. In this study, we used RNA sequencing to examine tumours from three experimental DFT1 cases. Two devils received a vaccine prior to inoculation with live DFT1 cells, providing an opportunity to explore changes to DFT1 cancers under immune pressure. Analysis of DFT1 in the non-immunised devil revealed a ‘myelinating Schwann cell’ phenotype, reflecting both natural DFT1 cancers and the DFT1 cell line used for the experimental challenge. Comparatively, immunised devils exhibited a ‘dedifferentiated mesenchymal’ DFT1 phenotype. A third ‘immune-enriched’ phenotype, characterised by increased PDL1 and CTLA4 expression, was detected in a DFT1 tumour that arose after immunotherapy. Mesenchymal plasticity and upregulation of immune checkpoint molecules are strategies used by human cancers to evade immune responses. Our results show that similar mechanisms are associated with immune evasion by DFTD cancers, providing novel insights into DFTD survival that will inform the development of effective DFTD vaccines.