Abstract B025: p53 responsive endogeneous retrovirus as early mediators of immunosurveillance

Triggering the immune system to attack the cancerous cells is the overarching goal of cancer immunotherapy. The key aspect of cancer immunosurveillance theory argues that our immune system acts as sentinels in recognizing and destroying the newly transformed cells that are continuously arising in vivo. Immediately after an oncogenic assault, the cell fires up various intrinsic cellular mechanisms in response to the genotoxic stress. This includes activation of DNA damage response proteins, senescence programs and tumor suppressor genes. These intrinsic responses have to be linked to the extrinsic mechanisms leading to activation of different components of the immune system. This intimate relationship between the intrinsic and the extrinsic mechanisms help to maintain tissue homeostasis and prevent further deleterious effect to the organ. However, very little is known about the critical molecular players that touch off the activation of immune system following the intrinsic response elicited by a genotoxic stress, for example, activation of tumor suppressor. These key molecular intermediaries should ideally possess the following features: 1) their expression should be upregulated in response to cellular stress 2) their upregulation should lead to a distinct immune response in vivo. We have recently identified a molecule that fits both of these criteria. We discovered a murine endogenous retrovirus (ERV) whose expression is dependent on the activity of p53. We found that components of this ERV are sufficient to induce changes in cell viability. It is characterized by a domain which is found in human T-cell leukemia virus type 1, a retrovirus found in blood cancer patients and are known to cause chronic inflammation. We found that this protein domain family is endogenized in the genomes of multiple vertebrates, including humans, potentially highlighting the evolutionary and functional significance of this element. Functional analysis of the murine ERV and homologous human ERV components suggest that these endogenous retroviral elements are early transducers of oncogenic stress, which brokers an immune response at the earliest stage of cellular transformation. We propose that these ERV components play a critical role in developing the immunogenicity against cancer, and may illuminate the mechanistic details of the first few events leading to activation of immune response following an oncogenic assault. Till recently, ERVs have been relegated as a part of the so-called ‘junk DNA’. Only recently have researchers begun revisiting this field to find the significance of ERVs in vertebrate biology. Our work sheds new light on the potential role of ERV remnants in response to neoplastic transformation. Citation Format: Kojiro Tashiro, Robyn Leary, Anindya Bagchi. p53 responsive endogeneous retrovirus as early mediators of immunosurveillance [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B025.