A Novel Immune Tolerization Strategy for Investigating the Trade-offs between Oncogene Pathogenicity and Immunogenicity.

PROJECT SUMMARY Genetic alterations triggering oncogene activation can produce neoantigens, rendering transformed cells vulnerable to immune assault. Under heightened immune pressure these cells must balance growth with immune evasion, offering a potential therapeutic avenue for early malignant cell targeting. However, the identification and study of distinct alterations contributing to immune evasion independently of tumor growth is hindered by the absence of immunocompetent models capable of separating oncogene-driven tumorigenesis from the associated immune responses. To overcome this barrier, we developed RECON, a novel immune tolerization strategy to convert transgenic proteins that may be recognized as “non-self” into self-antigens. RECON enables the use of foreign elements in the context of an intact immune system via ubiquitous expression of these elements, at the same time utilizing a dual-transcriptional/translational control system to suppress endogenous transgene levels and activity (e.g. luminescence, oncogenic transformation). Utilizing RECON's dual transgene tolerizing-suppressing effects on immunogenic oncogenes, we hypothesize that we can uncouple an oncogenes pathogenic potential from its immunogenic properties, enabling for dissection of the distinct genetic and phenotypic alterations that govern immune evasion independently of tumorigenesis during the earliest stages of cancer pathogenesis. Understanding these molecular events will shed light on how cells expressing non-native elements achieve enhanced immune evasion, thereby advancing our comprehension of cancer progression and potentially exposing new therapeutic strategies for early disease targeting. RECON presents a unique opportunity to explore oncogene-driven tumorigenesis within experimentally modified immune environments. It stands to generate fundamental insight into the trade-offs between tumorigenicity and immunogenicity during tumor progression and evolution. Overall, the RECON model represents a promising advancement in scientific research, offering a versatile solution that addresses existing limitations while extending the utility of diverse transgenic elements to various model organisms with intact immune repertoires.