Restoring MHC-I Molecules to Potentiate Immunotherapy in Uterine Cancer

Abstract

Uterine cancer is the 4th most common cancer among women, with about 66,570 new cases in the United States every year. Late-stage uterine cancer patients have a less than 20% chance of survival due to limited effectiveness in treatment options. Immunotherapy is an emerging type of cancer treatment; however, it is only effective in a subtype of uterine cancer (∼20%). Major histocompatibility complex I (MHC-I) molecules have been researched as a main mechanism assisting cancerous cells to evade death by immune cell destruction. The goal of this project is to identify molecular regulators of MHC-I in uterine cancer to aid immunotherapy. Here, we analyzed the prognostic value of MHC-I molecules based on patient and molecular datasets from The Cancer Genome Atlas. MHC-I combined with T cell markers is associated with better prognosis in uterine cancer. Two molecular candidates, interferon regulatory factor 1 (IRF1) and proteasome subunit beta type-9 (PSMB9), were identified as potential MHC-I regulators. Wet-lab experiments confirmed the role of IRF1 in regulating MHC-I expression, though PSMB9 was found to be ineffective. Furthermore, uterine cancer expressed lower levels of IRF1 compared with normal uterine tissues. This finding brings significant insight into a potential immunotherapy target molecule for treating uterine cancer. Future development includes direct testing of T cell immune responses with IRF1 enhancements to prove its effectiveness on immune cell action.