The Perfect Storm: Viral Mimicry Meets Cancer Dark Matter

The central mechanism for immune recognition of cancer remains a subject of debate. Some theories emphasize the importance of cancer antigen specificity and immunogenicity while others focus on innate chemo attractive and immune-modulatory properties of cancer cells. The immune system evolved under strong selection to protect individuals during their reproductive years from infectious epidemics, which helped to preserve species. Since common cancers often occur after the reproductive stage of life, there is less evolutionary pressure to eliminate them as they do not pose a direct threat to the survival of the species. So, why does the immune system care about cancer? The answer may be simpler than what has been conjectured in the past: the neoplastic process deviates sufficiently from normal tissue physiology to slowly align its phenotype to that of pathogen-infected cells. Simply put, cancer cells look infected to the immune system. Epigenetic alterations germane to cancer cell biology lead to aberrant production of nucleic acids and peptides recapitulating those produced by pathogen-infected cells. This results in two phenomena: (a) production of double stranded nucleic acids that trigger cancer cell intracellular sensors that consequently activate innate immunity; and (b) aberrant production of peptides from genomic regions silenced in normal cells or cancer-specific alteration of cellular processes. The former phenomenon is referred to as “viral mimicry” while the latter is referred to as “dark matter”. The symbiotic interplay between the two phenomena and their causality is the subject of this review.