Comparative Immunogenomics of Osteosarcoma: Developing Tools to Enable Prediction of DLA-Neoantigen Binding in Dogs in Order to Understand Immunotherapy Response across Species
Osteosarcoma is a rare and aggressive bone cancer that not only affects children, but also commonly occurs in pet dogs. The current therapies for this cancer have remained unchanged since 1984. Survival of osteosarcoma is very poor with 5-year survival rate of 70% and 27.4% for non-metastatic and metastatic human patient respectively. New treatments based on growing genomic understanding of the disease across species are sorely needed. One promising cancer treatment approach is immunotherapy, which enables the patient’s own immune system to identify and combat tumor cells. Certain types of immunotherapy have been shown to dramatically extend patient survival in some human cancers such as melanoma and lung cancer, but they have yet only shown limited efficacy in pediatric cancers like osteosarcoma. As we seek to improve immunotherapy responses in osteosarcoma, canines are ideal natural models to study immunotherapy efficacy, since they are immunocompetent, readily available, recapitulate the human disease and are exposed to the same environment as their human owners. Our goal was to sequence the DNA from dogs with naturally occurring osteosarcoma to predict interactions between and individual dog’s antigen-presentation machinery (Dog Leukocyte Antigen or DLA) and predicted mutant peptide products of DNA sequence alterations (putative neoantigens). The tools developed here may help inform understanding of the host response to immunotherapy and set a stage for rapid translation to human medicine. Using multi-platform sequencing techniques (whole exome sequencing and targeted DLA sequencing) followed by peptide and affinity prediction bioinformatic tools (BLASTX and netMHCPan, respectively) we identified tumor derived peptides with varying affinities for each dog’s DLA. A strong affinity of a large number of putative neoantigens for DLA is the primary correlate of patient response to immunotherapy in humans. Our results provide a proof of principle that we are able to perform DLA-neoantigen predictions in canine osteosarcoma and are thus an important step closer to broader profiling of immunogenomic landscapes in the setting of immunotherapy response.