Abstract PR14: Epidermal neoplasms bypass immune evasion requirements via niche occupancy

Abstract

Abstract Anti-tumor immune effectors exert selective pressure against transformed clones, ultimately permitting only mutation cascades that are either non-immunogenic or include immune-evasive adaptations. This evolutionary process often includes an equilibrium phase during which immunogenic transformed cells are prevented from outgrowth by the immune system without being eliminated. In most cases, escape from this state requires loss of antigen presentation and consequent loss of immunogenicity. To characterize this pre-outgrowth phase of cancer-immune interaction and test the efficacy of interventions during dormancy, we assembled a genetically-engineered mouse model (GEMM) of inducible, Kras-driven carcinogenesis coupled to a fluorescent reporter. Early characterization of this model revealed a confounding artificial tolerance mechanism that renders inducible alleles automatically non-immunogenic in autochthonous settings. To circumvent this tolerance, we transplant dissociated epidermal keratinocytes from the GEMM onto recipient animals that do not carry the inducible mutant Kras allele. This transplant step also enables the use recipient animals carrying various immune deficiencies. After graft healing, transformation is induced and the grafts are imaged repeatedly over time via intravital confocal microscopy. In immunocompromised recipients, transformation initiates the rapid growth of labeled cells and subsequent tumor formation. In immunocompetent cohorts, tumor formation does not occur. Instead, we observe establishment of a long-term equilibrium phase characterized by cyclic growth and regression of labeled clones originating exclusively from hair follicles, suggesting that the immune privilege of this stem cell niche provides a safe harbor for transformed cells. Surprisingly, the architecture of the normal tissue defines a protected reservoir for the survival of transformed cells, a fate that usually requires cell-intrinsic immune-evasive adaptations. This provides a mechanism by which a single source of anti-tumor activity could produce the observed biphasic nature of cancer-immune interaction, including both elimination of some clones and immune-mediated dormancy of others. Most importantly, we have identified a novel pre-malignant, immune-controlled state that may represent a vulnerable target population for rational cancer prevention strategies. Citation Format: Brad Kubick, Dennis Roop. Epidermal neoplasms bypass immune evasion requirements via niche occupancy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR14.