Oncogenic Stress is a Novel Immunogenic Signal Driven by the Unfolded Protein Response and Detected by Neutrophils

Cellular transformation is initiated by a driver mutation, resulting in the abnormal expression of an oncogene or the loss of a tumor suppressor gene in a normal cell. This event leads to oncogenic stress (OS), describing a disruption of cellular homeostasis which activates stress response pathways and transcriptomic programs that can either promote tumor development or trigger intrinsic safeguards such as senescence or apoptosis. While the immunogenicity of senescent cells is well established, the immunogenic potential of cells at the early OS stage and the mechanisms by which they are sensed by the immune system remain unknown. We developed an original in vitro OS model using primary human mammary epithelial cells to investigate this process. Our results show that OS cells display an immunoactive secretome associated with OS (SOS), as well as immunogenic membrane ligands. Intrinsically, OS cells activate the PERK and IRE1 branches of the unfolded protein response (UPR) that regulate their immunogenic features. Extrinsically, we demonstrated that neutrophils can detect OS-induced immunogenic signals, leading to their recruitment and their activation in co-culture in vitro . We validated this observation in two spontaneous murine models of breast cancer, where the earliest preneoplastic stages exhibit both UPR activation in epithelial cells and neutrophil infiltration. Altogether, our work identifies OS as the first immunogenic event in carcinogenesis and neutrophils as the first immune cell involved in immunosurveillance, paving the way for potential therapeutic approaches intercepting early steps of tumorigenesis.