JMJD2D Induces PD-L1 Expression To Promote Tumor Immune Escape By Enhancing IFNGR1-STAT3-IRF1 Signaling

Colorectal cancer(CRC)is one of the most common gastrointestinal tumors in human beings.The traditional treatment has limited efficacy and low survival rate.The survival time of many patients with advanced cancer has been prolonged with the development of tumor immunotherapy and the discovery of related immune checkpoint inhibitors,indicating that tumor immunotherapy is expected to become one of the important means of tumor treatment.Programmed death receptor-1(PD-1)has been widely concerned,which is one of the key molecules to inhibit the overactivation of immune response;PD-L1 is one of the important ligands of PD-1,which is highly expressed on tumor cells.It interacts with PD-1 on the surface of CD8+T cells and inhibits the activation and proliferation of CD8+T cells,thus avoiding immune system clearance.At present,there are still many limitations in tumor immunotherapy,such as narrow application range,insensitivity of patients,poor prognosis and large side effects.The prevention and treatment of CRC is one of the major issues to be solved in the field of medicine,however the effective targeted drugs for CRC are still lacking.We previously reported that JMJD2D promoted the development of CRC through Wnt/β-Catenin,Hedgehog and HIF signaling pathways,however,the role of JMJD2D in cancer immune escape is unknown.To clarify the molecular mechanism of CRC immune escape is significant for exploring the effective targeted therapeutic drug of CRC.In this study,we found that PD-L1 and JMJD2D were overexpressed in tumor tissues of CRC patients,which have a positive correlation;JMJD2D promoted immune escape of CRC by enhancing IFNGR1-STAT3-IRF1 signal to induce PD-L1 expression.Mechanistically,JMJD2D cooperated with the transcription factor SP-1 to induce IFNGR1 expression and cooperated with the transcription factors STAT3 and IRF1 to induce PD-L1 expression.Treatment of CRC-bearing mice with the PD-L1 antibody enhanced TNFα secretionby CD8+T cell,which induced JMJD2D expression to enhance IFNGR1-STAT3-IRP1 signaling and PD-L1 expression in tumors;Treatment of CRC-bearing mice with 5-c-8HQ reduced PD-L1 expression,stimulated CD8+T cell activation,and synergized with PD-L1-antibody-mediated cancer immunotherapy.These results demonstrate that JMJD2D promotes CRC immune escape by enhancing IFNGR1-STAT3-IRF1 signaling to induce PD-L1 expression and mediates the feedback upregulation of PD-L1 during PD-L1 antibody treatment,implicating that JMJD2D is a novel molecular target for cancer immunotherapy.