Zhen Tao1, Shaohua Xu2, Hailong Ruan3, Tao Wang4, Wen Song4, Li Qian5, Ke Chen3. 1. Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer institute & Hospital, National Clinical Research Center of Cancer, Tianjin, China. 2. Department of Gynaecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. 3. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 4. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 5. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
Abstract
BACKGROUND/AIMS: Radiotherapy is the standard treatment option for advanced prostate cancer. Unfortunately, despite significant advances in radiation delivery, prostate cancer radioresistance occurs in a large proportion of patients undergoing radiotherapy. As a way to enhance radiotherapy effectiveness, research advances into the mechanisms regulating the immune response have revived interest in combination radiation and immune-based therapies. METHODS: miR-195/-16 family and PD-L1 levels were analyzed in samples from a GSE21032 data set. Kaplan-Meier analysis was used to evaluate the difference in biochemical recurrence-free survival associated with miR-195 and miR-16 expression. qRT-PCR and western blot were used to evaluate the miR-195, miR-16 and PD-L1 expression. Then, we used bioinformatics analysis and luciferase reporter assay to predict and confirm the miR-195 and miR-16 target gene. Finally, we elucidate the miR-195 and miR-16 function on immune evasion in the DU145/T cell co-culture model and syngeneic mouse model treated with radiotion through qRT-PCR, western blot, Flow cytometry and ELISA. RESULTS: High levels of miR-195 and miR-16 were positively correlated with the biochemical recurrence-free survival of prostate cancer patients. miR-195 and miR-16 were inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. Further mechanistic investigations revealed that miR-195 and miR-16 inhibited PD-L1 expression. Additionally, restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking PD-L1 expression. This synergistic effect of immunotherapy and radiotherapy was associated with the proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: Our data revealbiological and functional interactions between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.
BACKGROUND/AIMS: Radiotherapy is the standard treatment option for advanced prostate cancer. Unfortunately, despite significant advances in radiation delivery, prostate cancer radioresistance occurs in a large proportion of patients undergoing radiotherapy. As a way to enhance radiotherapy effectiveness, research advances into the mechanisms regulating the immune response have revived interest in combination radiation and immune-based therapies. METHODS:miR-195/-16 family and PD-L1 levels were analyzed in samples from a GSE21032 data set. Kaplan-Meier analysis was used to evaluate the difference in biochemical recurrence-free survival associated with miR-195 and miR-16 expression. qRT-PCR and western blot were used to evaluate the miR-195, miR-16 and PD-L1 expression. Then, we used bioinformatics analysis and luciferase reporter assay to predict and confirm the miR-195 and miR-16 target gene. Finally, we elucidate the miR-195 and miR-16 function on immune evasion in the DU145/T cell co-culture model and syngeneic mouse model treated with radiotion through qRT-PCR, western blot, Flow cytometry and ELISA. RESULTS: High levels of miR-195 and miR-16 were positively correlated with the biochemical recurrence-free survival of prostate cancerpatients. miR-195 and miR-16 were inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. Further mechanistic investigations revealed that miR-195 and miR-16 inhibited PD-L1 expression. Additionally, restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking PD-L1 expression. This synergistic effect of immunotherapy and radiotherapy was associated with the proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: Our data revealbiological and functional interactions between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.