Q. Tao1, M. Chen1, Z. Liu1, X. Xu1,2, L. Wei1, S. Ma1, Y. Huang1, X. Xie1, R. Liu1, M. Wu1, J. Yu1, and D. Chen1; 1Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 2The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, China
Purpose/Objective(s):As an important substrate of tumor glucose metabolism, glucose plays an important role in tumor metabolic reprogramming. Radiotherapy as a common means of tumor treatment, can directly kill cancer cells and reshaping the tumor immune microenvironment along with tumor metabolic reprogramming. However, the role of glucose in radiotherapy-mediated tumor immune microenvironment (TIME) reshaping and tumor metabolic reprogramming is still lacking. Therefore, our project aims to explore whether glucose supplementation can reshape tumor metabolism and enhance the efficacy of radiotherapy. Materials/
Methods: The clinical data of patients were investigated to explore the correlation between blood glucose level and prognosis. To simulate changes in patient blood glucose levels, we established subcutaneous tumor models using mouse tumor cell lines such as MC38, CT26, B16F10, and CMT167, which were subjected to radiotherapy of one fraction of 15 Gy with or without daily subcutaneous administration of glucose or saline to explore the effects of supplementing glucose on hypofractionated radiotherapy. Flow cytometry was subsequently used to assess TIME. Real-time qPCR and O2K was used to monitor changes of glucose metabolism in tumor cells. Relevant mechanisms were validated through RNA sequencing, flow cytometry, in vitro co-culture, O2K, real-time qPCR, and western blotting. Results: Through clinical data, it was found that within normal blood glucose levels, the prognosis of small cell lung cancer patients is significantly positively correlated with blood glucose levels. Various mouse subcutaneous tumor models have confirmed that supplementing glucose can enhance the efficacy of radiotherapy. Further analysis of flow cytometry confirmed increased infiltration and enhanced cytotoxic function of CD8+ T cells, thereby improving the TIME post-radiotherapy. Cell proliferation experiments demonstrated that supplementing glucose minimally impacted on radiotherapy-induced tumor cell proliferation and apoptosis. Furthermore, RNA sequencing and in vitro experiments confirmed that addition of glucose significantly enhanced activation of the IFN-I pathway after radiotherapy, which is depend on the increased levels of mitochondrial oxidative phosphorylation. While in the presence of oxidative phosphorylation inhibitors, boosted IFN-I pathway after radiotherapy by glucose addition disappeared. Further in vitro co-culture experiments showed that tumor cells cultured in high glucose levels post-radiotherapy promoted secretion of Cxcl10 of bone marrow dendritic cells. Conclusion: Our study found that glucose supplementation can enhance the efficacy of hypofractionated radiotherapy, which is partly attributed to activation of tumor oxidative phosphorylation and IFN-I pathway after radiotherapy, thus improving the tumor immune microenvironment.
