| First Author | Yang X | Year | 2020 |
| Journal | Cancer Immunol Res | Volume | 8 |
| Issue | 11 | Pages | 1440-1451 |
| PubMed ID | 32917658 | Mgi Jnum | J:360085 |
| Mgi Id | MGI:7797568 | Doi | 10.1158/2326-6066.CIR-20-0111 |
| Citation | Yang X, et al. (2020) Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol Res 8(11):1440-1451 |
| abstractText | The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated, and the suppressive tumor immune microenvironment must be considered. We investigated whether the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSC) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1alpha (HIF-1alpha) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1alpha/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1alpha in MDSCs reverted antitumor T-cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1alpha signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC. |
