Abstract B56: Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types

Variability in the immunogenic landscape of metastatic cancer lesions has revealed insight into detection of potential immunotherapy-responsive patients, though underlying mechanisms driving such variation are not fully understood. Endogenous retrovirus (ERV)-containing transcripts have recently emerged as a potential source of tumor-associated antigen that are orthogonal to somatic mutation-derived neoantigens. To characterize the intersection between ERV levels and predicted immunogenicity in metastatic cancer, we comprehensively profiled the transcript abundance of 702,533 ERV loci in 199 metastatic tumors from breast, colorectal, and pancreatic cancer patients. In all three cancer types, overall ERV transcript load was associated with upregulation of genes involved in innate antiviral response pathways as well as genes involved in both adaptive and innate immune signaling. In colorectal and pancreatic tumors, samples with concomitant increases in ERV load and antiviral response gene expression, termed viral mimicry tumors, showed high expression of the DNA demethylation gene TET2, a gene previously described to promote transcription of ERV-containing transcripts. Collectively, these data are compatible with the notion that an increased level of ERV-containing transcripts may account for increased immunogenicity in a subset of metastatic tumors and support the relationship between DNA demethylation and ERV load in colorectal and pancreatic tumors. Citation Format: James T. Topham, Emma Titmuss, Erin Pleasance, Laura M. Williamson, Joanna M. Karasinska, Luka Culibrk, Michael K.C. Lee, Steve E. Kalloger, Shehara Mendis, Richard A. Moore, Andrew J. Mungall, Janessa Laskin, Jonathan M. Loree, Dixie L. Mager, Marco A. Marra, Steven J.M. Jones, David F. Schaeffer, Daniel J. Renouf. Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B56.