Generation of repetitive element-specific T cells to target ovarian cancer

Abstract

Abstract The immunosuppressive tumor microenvironment in ovarian cancer (OC) enables these tumors to evade the immune system, resulting in late diagnosis and poor therapeutic outcomes for patients. This immunosuppression can be partially reversed with epigenetic inhibitors, which stimulate an immunogenic interferon response in OC cells by inducing the transcription of repetitive elements (REs). However, epigenetic therapy alone is not curative in clinical trials and new treatments that further augment the immune response to OC are needed. While REs are epigenetically silent in terminally differentiated cells, their increased expression in OC cells implicate these genomic elements as an unexplored pool of tumor antigens. As epigenetic therapy also upregulates antigen processing and presentation in OC cells, the generation of T cells specific for over-expressed RE-derived antigens may boost the immune recognition of OC cells. Transducing healthy donor T cells with a T cell receptor construct that recognizes the RE ERV-K-Env resulted in antigen specificity only when co-cultured with B lymphoblastoid cells derived from the same donor that the T cell receptor was isolated from. Transduced T cells were not specific for ERV-K-Env in autologous systems. As previous reports have shown that ERV-K-Env-specific T cells can only be expanded from patients with OC, current studies are underway to expand T cells from OC patients. Upon successful expansion of ERV-K-Env-specific T cells from multiple OC patients, we will assess if specific recognition is enhanced by treating autologous tumor cells with epigenetic therapy. These efforts serve as a novel approach to enhance the immune response to OC and improve the overall OC patient survival rate. NIH F31 CA271788-01 DOD W81XWH2010273